Next Article in Journal
Metabolic Niches and Plasticity of Sand-Dune Plant Communities Along a Trans-European Gradient
Previous Article in Journal
Impact of the Dietary Fat Concentration and Source on the Fecal Microbiota of Healthy Adult Cats
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Metabolites
Volume 15
Issue 4
10.3390/metabo15040216
metabolites-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Secondary Metabolites from Croton Species and Their Biological Activity on Cell Cycle Regulators

by
Jorge Augusto Alamillo-Vásquez
1,
Claudia-Anahí Pérez-Torres
2,*,
Enrique Ibarra-Laclette
1,
Feliza Ramón-Farías
3,
Pilar Nicasio-Torres
4 and
Fulgencio Alatorre-Cobos
5,*
1
Red de Estudios Moleculares Avanzados (REMAV), Instituto de Ecología, A.C. (INECOL), Carretera Antigua a Coatepec 351, Col. El Haya, Xalapa 91073, Veracruz, Mexico
2
SECIHTI-Red de Estudios Moleculares Avanzados (REMAV), Instituto de Ecología, A.C. (INECOL), Carretera Antigua a Coatepec 351, Col. El Haya, Xalapa 91073, Veracruz, Mexico
3
Facultad de Ciencias Biológicas y Agropecuarias, Universidad Veracruzana, Córdoba 94500, Veracruz, Mexico
4
Centro de Investigación Biomédica del Sur (CIBIS), Instituto Mexicano del Seguro Social (IMSS), Xochitepec 62790, Morelos, Mexico
5
SECIHTI-Unidad de Biología Integrativa Centro de Investigación Científica de Yucatán, A.C., Calle 43 No. 130 × 32 y 34, Col. Chuburná de Hidalgo, Mérida 97205, Yucatán, Mexico
*
Authors to whom correspondence should be addressed.
Metabolites 2025, 15(4), 216; https://doi.org/10.3390/metabo15040216
Submission received: 19 February 2025 / Revised: 16 March 2025 / Accepted: 21 March 2025 / Published: 23 March 2025
(This article belongs to the Special Issue Phytochemicals and Pharmacological Significance of Plant Secondary Metabolites in Medicine)
Browse Figures
Versions Notes

Abstract

:
Plant-based traditional medicine integrates beliefs, knowledge, and practices to prevent and treat multiple diseases. Croton is a large and worldwide-spread genus belonging to Euphorbiaceae, a family well known for comprising many species with medicinal properties due to its high diversity of phytochemical constituents with biological activities. Among the various benefits of Croton species in traditional medicine, its use in cancer treatment has recently received significant attention from the scientific community. This review provides a general overview of different studies on the Croton genus in the research for alternative cancer treatments and the impact of its secondary metabolite catalog on cell cycle targets. Our analysis indicates that just under 30 secondary metabolites have been identified so far in latex and extracts obtained from leaves, twigs, or bark from 22 different Croton species. Based on standard assays using cell lines or human platelets, these molecules show multiple biological activities mainly compromising cell viability and cell cycle progression, supporting the ethnobotanical use of Croton species for cancer treatment. Several studies indicate that Croton metabolites target CDK–cyclin complexes and signaling routes that trigger apoptosis; however, further studies are needed to better understand the molecular mechanisms underlying Croton metabolites’ effects and their accurate future applications in cancer treatment.

1. Introduction

The Euphorbiaceae family comprises nearly 322 genera and 8910 species, and is one of the most diverse groups of angiosperms. For example, in Mexico, this botanic family includes 782 species grouped into 43 genera, some with highly contrasting phenotypes, for example, Euphorbia, Croton, and Acalypha [1]. Although this family contains the most famous flower globally, Euphorbia pulcherrima Willd. Ex Klotzsch, commonly known as poinsettia, is also appreciated for its secondary metabolites, which have biological activities against pathogens, insects, pests, and predators, and expanded use in traditional medicine for human wellness. They also have varied applications in the rubber industry (Hevea brasiliensis Müll.Arg.) and the food industry (Manihot esculenta Crantz).
Croton is one of the largest genera within the Euphorbiaceae family, containing about 1300 species with contrasting phenotypes ranging from large woody trees to herbs, and habits that include tropical and temperate zones worldwide [2]. Considering the complexity of the Croton genus, which has been demonstrated by both classical taxonomy studies and phylogenetic analyses [3,4], it is undeniable that future studies based on high-throughput genotyping will be necessary to accurately identify the high diversity in the Croton species [5]. Interestingly, two-thirds of all the Croton species described so far are distributed in the New World, particularly in South America [6]. For example, C. lechleri Müll.Arg., the most studied Croton species, is found in the Amazon region at an altitudinal range of 705–1660 asl. This species has been widely studied in pharmacology due to its importance in folk medicine; native people from this region treat several illnesses, tumors, and cancers with this natural resource [7]. In the Neotropic area, Mexico harbors over one hundred Croton species and is considered an essential center of secondary diversification of this genus [8]. For instance, C. draco Schltdl. var. draco has been documented for its ethnobotanical uses in this country (Figure 1A–C). This species is distributed from the Gulf of Mexico to the Yucatan Peninsula at altitudes that reach up to 1700 asl. In contrast to C. lechleri, C. draco has been poorly investigated despite their close taxonomic relationship (Figure 1B), opening a new research field on the phytochemistry and pharmacology of both species. Although the uses of Croton species are extended in traditional human medicine worldwide, their application in cancer treatment has recently received significant attention from the scientific community, especially those species with secondary metabolites (SMs) with bioactivity against cell cycle regulators [9] (Figure 1D). The main aim of this review is to provide a general overview of different studies on the Croton genus in research on alternative cancer treatments and the impact of its secondary metabolite catalog on cell cycle progression.

Review Methodology

Relevant references were retrieved from PubMed, Web of Science, Springer, and Wiley Online Library databases from 1993 to 2025. The search terms included the words “Croton”, “anti-cancer/tumor”, “cell cycle”, “Tropical plant species”, “plant metabolites”, “apoptosis”, and “cancer combined with natural products”. The references in these articles were further checked to identify additional studies. Additionally, a brief search was carried out in Espacenet, Patentscope, and Google Patents using Croton as the keyword to identify developing novel inventions that meet patentability criteria in this topic.

2. Overview of Ethnopharmacological Uses of Croton Secondary Metabolites

Several Croton species produce red latex, commonly called “Dragon’s blood”. This crude extract is enriched with SMs such as taspine (the major component), tannins, diterpenes, and volatile oils [10]. Croton tree trunks, the preferential source of “Dragon’s blood”, contain laticifers and nonspecialized parenchyma cells that secrete latex in Croton species. The number of laticifers varies between species and depends on diverse factors such as plant age and environmental conditions [11,12]. Croton leaves are also an organ widely used in traditional medicine; however, it is not known what leaf tissues or cells produce the SMs that are potentially responsible for their biological activities.
Figure 2A shows the most common Croton species used in traditional medicine. These 18 species are distributed in Mexico, South America, Southern Africa, India, China, and Southeast Asia. In all of these countries, Croton species are an important resource for healing wounds [10,13,14]. They also act as anti-inflammatory agents [15,16,17] and treat respiratory and stomach illnesses [18], parasitic diseases [19,20,21,22], microbial infections [23,24,25,26], viral infections like hepatitis and herpes simplex [27,28,29,30], ulcers [31,32,33], diabetes [34,35,36,37], hypertension [38,39,40,41], rheumatic diseases [42,43], and cancer (Figure 2B) (for further studies focused on broader ethnobiological approaches and exploitation of scientific resources based on Croton species, we recommend other reviews available in the literature [10,44,45,46]). Because of the increasing impact on millions of human lives each year, research on Croton latex and the isolated SMs has focused on cancer, evaluating their effectiveness on cell proliferation and in vivo toxicity. The cancer types and cell lines evaluated include breast (MCF-7, BT474, MDAMB-435, and MDAMB-231), cervical (HeLa), gastric (AGS, Kato-3), colorectal (HT-29, SW-620, HCT-8, HCT-116, and SW-480), Leukemia (HL-60, K562, and CCRF-CEM), lung (NCI-H460, A549, and H1975), glioblastoma (SF-268 and SF-295), hepatocarcinoma (HEP-G2 and Huh-7), melanoma (SK23 and UACC62), and ovarian (OVCAR) (Figure 2B).
In line with the growing scientific interest in the Croton species, the number of patents for Croton-related use has also significantly increased in the last decade. Based on the search criteria, the results revealed approximately 20 patents per year in 2014–2020 compared with one per year in the 1990s. The patents protect protocols for fraction preparations, formulation methods, and use in areas such as pharmacology, cosmetics, and biotechnology. Interestingly, this emerging boom to protect the uses and innovations of Croton species is also occurring in countries that have long used Croton as an essential part of their traditional medicine (Figure 2C).

3. Molecular Targets of Croton Metabolites in Cancer

Cancer pathology is characterized by rapid cell proliferation beyond their boundaries; thus, this disease can invade other parts of the body, spreading malignancy caused by genetic alterations that modify cell cycle progression in different ways. Anticancer molecules approved for cancer therapy belong to natural plant products, such as irinotecan, vincristine, etoposide, camptothecin, and taxol [47]. As described above, Croton species are widely studied to determine their effects on several cancers. In at least 22 species, the biological activity observed has been associated with the crude extract (latex) or a specific isolated metabolite (Table 1, Figure 2 and Figure 3). Comprehension of the anticancer compounds’ activities and their molecular mechanisms of action is crucial to ensuring their safety in further clinical studies [48]. Several compounds found in Croton species have been evaluated for their role in fighting cancer by targeting cell cycle pathways (Table 1 and Figure 3). Most of the studies are focused on analyzing the role of these metabolites in cell cycle arrest and apoptotic pathways, with solid evidence in these processes. Following, we summarize what is known about these Croton SMs and the mechanisms involved in their use in cancer studies.

Cell Cycle Arrest and Apoptotic Induction

The cell cycle represents a tightly programmed event that leads to a cell duplicating its content, mainly characterized by DNA replication and segregation of replicated chromosomes to generate two identical daughter cells. This process includes two principal differential stages: mitosis and interphase. Mitosis refers to the proper cell division that comprises prophase, metaphase, anaphase, and telophase. On the other hand, the interphase is the most extended phase of the cell cycle; during this time, the cell grows and replicates DNA in preparation for mitosis. The cell grows in size and volume before (G1 phase) and after (G2 phase) DNA synthesis (S phase). After cell division, some cells enter a non-replicative phase designated G0. This state can be temporary or definitive, as cells can rest in a cell cycle or be fully differentiated.
Cyclin-dependent kinases (CDKs), a family of serine/threonine protein kinases, control cell cycle progression in all eukaryotes. CDK activity is positively and negatively regulated by phosphorylation by protein subunits called cyclins, which bind to CDKs and generate a regulator complex. In addition to cyclins, other inhibitory and scaffolding proteins also join this complex to ensure specificity and subcellular localization. Because they control cell cycle progression, these key components are targets in the search for cancer therapies since their expression in cancer cells is compromised; therefore, their regulation could induce cell death [78]. Progression through G1/S is led by the CDK–cyclin complex that regulates the retinoblastoma protein/E2F (RB/E2F) pathway, which is crucial in regulating cell cycle gene expression. Increased intracellular levels of cyclin D lead to the formation of CDK4–cyclin D and CDK4–cyclin D complexes, which phosphorylate the retinoblastoma protein (RB) [79]. The activity of the E2F transcription factor, whose products are required for S phase progression, is repressed by RB. To progress through G1/S, hyperphosphorylation of RB protein by the action of the CDK2–cyclin E complex has to take place in late G1. Therefore, RB/E2F members are cell cycle regulators. Beyond this restriction point, the CDK1–cyclin A complex keeps RB phosphorylated, ensuring the S phase. Genetic alterations of molecular determinants involved in the G1-S transition are present in different cancer types, allowing cells to proliferate independently. Therefore, discovering and studying new inhibitors of cell regulators such as CDKs is a hot point in the search for anticancer therapeutics [80].
Croton latex and isolated SMs have been evaluated to assess their in vitro effectiveness against the proliferation of cell lines, identifying molecular targets throughout cell cycle progression. In the initial stages of the cell cycle, B10G5, a naturally occurring phorbol ester isolated from C. tiglium (Figure 3), increases apoptosis and leads to decreased levels of cyclin D1 in the NSCLC lung cancer cell line [71]. As cyclin D1 is required for G1/S progression and cyclin D overexpression is associated with tumor growth [81], B10G5 represents a promising SM for developing a specific cancer therapy targeting this phase.
In addition to modulating cyclin D1 levels, B10G5 activates the protein kinase C (PKC) pathway [71]. The activities of the genes involved in this pathway are generally compromised in many types of cancers, usually due to the suppression of their expression levels [82]. B10G5 affects the anti-proliferation of lung tissue cells, including apoptosis and cell cycle arrest in the G2/M phase, by activating PKC-mediated signaling pathways and downregulating cyclin B1, matching PKC roles in cellular functions such as proliferation, G2/M activity, and cyclin B1 modulation [83].
Taspine, an alkaloid first isolated from Radix et Rhizoma Leonticis, has become an important natural resource due to its extensive pharmacological activities. Interestingly, taspine is a major constituent of latex in some Croton species, representing up to 7–9% of latex dry weight (Figure 3) [84,85]. This alkaloid directly affects CDK2 and CDK4, key players in the early stages of the cell cycle. Treating the A431 cell line, a clinical model of epidermal carcinoma, with taspine metabolite altered CDK2/CDK4 levels and compromised G1/S transition, leading to BCL-2 downregulation and causing apoptosis and cell cycle arrest at G1/S transition [86] (Figure 4). BCL-2 family proteins play a pivotal role in regulating cell apoptosis due to their ability to form membrane channels in mitochondria. The proteins can be classified into two subfamilies: pro-apoptotic members (BCL-2, MCL-1) and anti-apoptotic members (BAX, BAK, BAD) [87]. Localized to the outer membrane of mitochondria, BCL-2 has a significant impact on mitochondrial integrity. Thus, Croton taspine could positively affect cancer treatment by affecting cell proliferation and apoptosis. In line with this idea, it has been proposed that apoptosis induced by Croton taspine is caused by the expression of specific genes with action patterns similar to topoisomerase inhibitors such as ellipticine and camptothecin [54]. Topoisomerases are enzymes involved in DNA supercoiling, a key point for cell replication. Indeed, taspine induces an accumulation of cells undergoing S and G2 phases of the cell cycle, similar to what topoisomerase inhibitors do (Figure 4).
Due to the importance of taspine demonstrated in recent years, attempts to improve solubility have led to a new taspine derivative, TPD7 [88], which has antiproliferative activity in cutaneous T cell lymphoma H9. TPD7 significantly decreased the levels of the anti-apoptotic BCL-2 and MCL-1 proteins and increased the levels of the pro-apoptotic BAX, BAK, and BAD proteins and, interestingly, P53, a tumor suppressor gene in H9 cells. Thus, the effect of TPD7 in inhibiting H9 cell viability appears to be mediated by induction of cell cycle arrest and increased cell apoptosis through the mitochondrial pathway. Additionally, TPD7 targets cell cycle regulators, such as CDC2 (CDK1), cyclin D1, and cyclin E1, which are essential in the G1/S transition, and cyclin B1, which is associated with the G2/M checkpoint. Although further research is required, these results show that Croton taspine and TPD7 provide insights for regulating cell cycle regulators (Figure 4), a key aspect during cancer treatment.
Further assays using confocal microscopy demonstrated that taspine increased acetylated α-tubulin, which is a marker of stable, long-lived, nondynamic microtubules [89,90,91] that trigger morphologic changes in the human melanoma SK23 cell line, suggesting its molecular action on specific targets in the cytoskeleton (Figure 4).
The diterpenoid ent-kaurane I, isolated from the twigs and leaves of C. kongensis, was evaluated for its cytotoxic activity against five human tumor cell lines. Biological tests showed that this compound possesses strong anti-proliferation activity, arrests the cell cycle at the G2/M phase, and induces apoptosis of MDA-MB-231 breast cancer cells [77]. Mitochondria may produce more ROS because mitochondrial function is weakened by MMP depolarization, and the excessive ROS may be involved in the regulation of cell apoptosis. Investigation of its mechanism showed that ent-kaurane I can inhibit tumor proliferation and migration by targeting mitochondria to increase intracellular reactive oxygen species (ROS) and regulating STAT3 and FAK signal pathways. Collectively, these findings support the great potential of this compound as an anticancer agent [77].
Natural antioxidants, such as phenols, tannins, and flavonoids, in the acetonic fraction of C. bonplandianus leaf extracts (AcE), exhibit anticancer activity against lung tumor cell lines. Treatment with AcE leads to cell cycle arrest in G2/M and cell death induction. Although further experimental research is needed to understand the molecular mechanisms, attempts to scavenge free radicals—commonly associated with the process and progression of cancer—using natural antioxidant sources could be an alternative strategy for treating cancer [65]. Another Croton metabolite evaluated in cancer research is plaunotol, a diterpene isolated and found only in C. stellatopilosus [70]. It acts as an apoptotic agent in breast, cervical, and colon cancers. Plaunotol exhibited antiproliferative activity during the G0/G1 phase in HeLa cells, while in the HT-29 line, a similar effect was observed in G2/M, leading to apoptosis in both cases (Figure 4). Expression profiling analysis showed that this Croton metabolite induced BCL-2 downregulation, similar to that previously found for taspine, which may explain cell death through mitochondrial-dependent pathways observed in the tested cell lines.
Another SM that induces G2 arrest and prevents mitotic entry is [1–9-NαC]-crourorb A1 [67], a cyclic peptide isolated from C. urucurana. The viability of Huh-7 (human hepatocarcinoma) cells treated with this peptide was compromised in a dose- and time-dependent manner, and was associated with the induction of apoptosis. The effects of crourorb A1 associated with G2/M arrest were due to changes in CDK1, cyclin B1, and P53 expression. Crucial checkpoints comprise activation of tumor suppressor gene P53 guided by DNA damage transducer kinases—ataxia telangiectasia mutated (ATM), Ataxia telangiectasia/Rad3 related (ATR), and checkpoint kinases CHK1 and CHK2—preventing CDK1–cyclin B activation and mitotic entry. P53 and G2/M modulation by [1–9-NαC]-crourorb A1 highlights the importance of the biological activity of natural cyclic peptides from Croton species in cancer cell lines [67].
Another report focused on the inhibition of oral squamous carcinoma cells (HNSCCs) and their radiosensitization by the NCKU_PCK_0001 compound isolated from C. tonkinensis [58]. This compound reduced cell viability, migration, and invasion by downregulating the AKT/mTOR signaling pathway and its mediators, such as pAKT (ser473), p-mTOR (ser2448), and PI3K, a heterodimer comprising two distinct subunits: the regulatory subunit p85 and the catalytic subunit p110α. Dysregulation of these proteins drives cancer development and progression [92,93,94]. Blocking this pathway modulates checkpoint kinase 2 (CHK2) activity and the resulting effects on (CDK1)/cyclin B1 activity as its potential mechanism on cell cycle [95]; thus, cell cycle arrest is the major mechanism of radiation sensitization associated with PI3K/mTOR inhibition by NCKU_PCK_0001 in HNSCCs. This suggests that compounds derived from C. tonkinensis could potentially improve the effectiveness of radiotherapy, especially in overcoming radioresistance, which is a common challenge in cancer treatment [58].
Natural Croton oils also potentially affect the development of cancer treatments; for instance, C. crassifolius Geisel essential oil (CCEO) induces cell cycle arrest in A549 lung tumor cells. The molecular targets of CCEO are cyclin B1-CDK1 and cyclin A-CDK1. CCEO acts by decreasing their expression levels and, in contrast, increasing cyclin-dependent kinase inhibitor (CKI) P21 expression [73]. Similarly, treating the A549 lung cancer cell line with C. tiglium essential oil (CTEO) altered the expression levels of cyclin B1, cyclin A, and CDK1 [72]. This triggered cell growth inhibition, with significantly enhanced P21 levels. P21 inhibits the activities of CDK2 and CDK4 in a P53-dependent or independent manner. Lastly, P53 can act as an oncogene, promoting tumor evolution by accumulating DNA damage. Determining the correct role of P21 in preventing cancer progression has been challenging in cancer research [96].
Chettaphanin II, isolated from C. crassifolius root extracts, recently showed a reduction in A549 human lung carcinoma cell proliferation and induced G2/M phase arrest, resulting in cytotoxicity and apoptosis [74]. Chettaphanin II significantly inhibited tumor growth in experiments performed on naked mice. The antitumor mechanism of chettaphanin II involves blocking the mTOR/PI3K/Akt signaling pathway in the A549 cells. Molecular docking established that chettaphanin II can bind to the active sites of BCL-2 and BAX. This report confirmed that chettaphanin II has strong tumor inhibition ability in vitro and in vivo, indicating its potential application in anticancer therapy [74].
The centrosome cycle occurs parallel to the cell cycle and is regulated by mitotic kinases such as CDK1 through spindle apparatus formation. During G2/M, the CDK1–cyclin B1 complex is activated to initiate M through chromosome condensation and microtubule dynamics regulation. To ensure the integrity of the genetic material at the end of the cell cycle, there are checkpoints to repair DNA damage that commonly occurs during the process and then activate cell arrest [97]. At this cell cycle point, one of the proposed mechanisms underlying apoptosis induced by C. palanostigma latex treatment is perturbations in microtubule structure adhesion and reassembly. Studies have reported that cancer cells undergo blockage upon exposure to latex during the late G2 phase of the cell cycle. Characteristic apoptotic changes, such as chromatin condensation and nucleus contraction, were evident within a few hours of treatment, resulting in non-functional microtubules being unable to adhere and leading to cell apoptosis [51].

4. Perspectives and Conclusions

The vast chemical diversity of the Croton genus is comparable with the number of its species, which represents a unique opportunity in the quest for novel anticancer agents. Mining the current literature during the writing of this review indicated that less than 5% of the known Croton species have been included in bioprospection metabolite studies. The pharmaceutical potential of the Croton genus is particularly significant for countries rich in these species; this is reflected in the increase in Croton-use-related patents claimed by countries harboring Croton species.
Croton latex and isolated SMs have been evaluated to assess their in vitro effectiveness against proliferation in cell lines and in vivo toxicity. Cancerous cells are well known for their capacity to maintain proliferative signaling, mainly via mutations that prevent apoptosis and cell cycle exit. Understanding how malignant cell machinery acts can unveil susceptible steps that could be targeted for new drug development. Compelling evidence collected so far shows that several Croton SMs exert biological activity against diverse and specific targets on cell cycle progression and signaling pathways triggering apoptosis; however, other molecular mechanisms or metabolic processes underlying their anticancer properties are still missing. For example, the role of phenolic compounds, enriched in the Croton latex, on redox homeostasis disruption or glucose transporters (GLUCTs) in cancerous cells is almost unknown. Epigallocatechin gallate from green tea is reported to decrease GLUT1 mRNA levels in colon cancer cells; gallocatechin has been found in C. celtidifolius; thus, a link between Croton SMs and GLUCTs is plausible. Other questions remain open about compounds like crotobarin, crotogoudin, crotonkinins, or the flavonoids rutin and vitexin, already reported in Croton species. The last flavonoid, vitexin, is a potential drug for nasopharyngeal carcinoma. Cell energy metabolism could be another hot research topic in Croton, especially in the mitochondrion, as reprogramming energy metabolism is one of the hallmarks of cancer therapy. Effects of Croton compounds on tubulin and actin have also been reported; regulation of the cytoskeleton plays a key role in cancer cell migration and invasion; thus, research in this field could provide insights into Croton SMs’ benefits in controlling cancer.
Given the significant heterogeneity among cancer types, even within the same tissue, it is imperative to understand in depth the mechanisms of action of each metabolite, including their specific molecular targets within the cell cycle and other metabolic processes. By addressing these challenges, the lack of insight into the clinical stages of Croton SMs can be solved, impacting the development of cancer precision medicine.

Author Contributions

Conceptualization, C.-A.P.-T. and F.A.-C.; writing—original draft preparation, J.A.A.-V. and C.-A.P.-T.; writing—review and editing, E.I.-L., F.R.-F. and P.N.-T.; supervision C.-A.P.-T. and F.A.-C. All authors have read and agreed to the published version of the manuscript. All authors contributed to the final manuscript’s design and writing, revision, and approval.

Funding

This research was funded by Secretaría de Ciencia, Humanidades, Tecnología e Innovación (SECIHTI) through “Ciencia de Frontera 2023—Firmas de expression genética para el diagnóstico y predicción del estado nutricional en plantas: una estrategia para potenciar el uso de fertilizantes encapsulados”, with grant number CF-2023-G-947 also awarded by SECIHTI to C.-A.P.-T.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

Jorge A. Alamillo-Vásquez thanks SECIHTY for the Ph.D. scholarship (592645).

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
CDKCyclin-dependent Kinase
SMsSecondary metabolites
RBRetinoblastoma protein

References

  1. Villaseñor, J.L. Checklist of the native vascular plants of México. Rev. Mex. Biodivers. 2016, 87, 559–902. [Google Scholar] [CrossRef]
  2. Govaerts, R.; Frodin, D.G.; Radcliffe-Smith, A.; Carter, S. World Checklist and Bibliography of Euphorbiaceae (with Pandaceae); The Royal Botanic Gardens, Kew: Richmond, UK, 2000; Available online: http://catalog.hathitrust.org/api/volumes/oclc/44041175.html (accessed on 29 May 2024).
  3. Berry, P.E.; Hipp, A.L.; Wurdack, K.J.; Van Ee, B.; Riina, R. Molecular Phylogenetics of the Giant Genus Croton and Tribe Crotoneae (Euphorbiaceae Sensu Stricto) Using ITS and TRNL-TRNF DNA Sequence Data. Am. J. Bot. 2005, 92, 1520–1534. [Google Scholar] [CrossRef] [PubMed]
  4. Webster, G.L. A Provisional Synopsis of the Sections of the Genus Croton (Euphorbiaceae). Taxon 1993, 42, 793–823. [Google Scholar] [CrossRef]
  5. Osathanunkul, M.; Suwannapoom, C.; Ounjai, S.; Rora, J.A.; Madesis, P.; De Boer, H. Refining DNA Barcoding Coupled High Resolution Melting for Discrimination of 12 Closely Related Croton Species. PLoS ONE 2015, 10, e0138888. [Google Scholar] [CrossRef]
  6. van Ee, B.; Riina, R.; Berry, P. A Revised Infrageneric Classification and Molecular Phylogeny of New World Croton (Euphorbiaceae). Taxon 2011, 60, 791–823. [Google Scholar] [CrossRef]
  7. Alonso-Castro, A.J.; Ortiz-Sánchez, E.; Domínguez, F.; López-Toledo, G.; Chávez, M.; Ortiz-Tello, A.D.J.; García-Carrancá, A. Antitumor Effect of Croton lechleri Mull. Arg. (Euphorbiaceae). J. Ethnopharmacol. 2012, 140, 438–442. [Google Scholar] [CrossRef]
  8. Steinmann, V.W. A Synopsis of Croton (Euphorbiaceae) in Michoacán, Mexico. Taxonomy 2021, 1, 395–424. [Google Scholar] [CrossRef]
  9. Sharma, V.; Kumar, D.; Dev, K.; Sourirajan, A. Anticancer Activity of Essential Oils: Cell Cycle Perspective. S. Afr. J. Bot. 2023, 157, 641–647. [Google Scholar] [CrossRef]
  10. Salatino, A.; Salatino, M.L.; Negri, G. Traditional Uses, Chemistry and Pharmacology of Croton Species (Euphorbiaceae). J. Braz. Chem. Soc. 2007, 18, 11–33. [Google Scholar] [CrossRef]
  11. Jura-Morawiec, J.; Tulik, M. Dragon’s Blood Secretion and Its Ecological Significance. Chemoecology 2016, 26, 101–105. [Google Scholar] [CrossRef]
  12. Ramón, F.; Williamson, J.S.; Rodríguez, S.V.; Angeles, G.; Portugal, V.O. Bark Anatomy in Croton draco Var. Draco (Euphorbiaceae). Am. J. Bot. 2009, 96, 2155–2167. [Google Scholar] [CrossRef]
  13. Casao, T.d.R.L.; Pinheiro, C.G.; Sarandy, M.M.; Zanatta, A.C.; Vilegas, W.; Novaes, R.D.; Gonçalves, R.V.; Viana Leite, J.P. Croton urucurana Baillon Stem Bark Ointment Accelerates the Closure of Cutaneous Wounds in Knockout IL-10 Mice. J. Ethnopharmacol. 2020, 261, 113042. [Google Scholar] [CrossRef] [PubMed]
  14. Murillo, R.M.; Jakupovic, J.; Rivera, J.; Castro, V.H. Diterpenes and Other Constituents from Croton draco (Euphorbiaceae). Rev. Biol. Trop. 2001, 49, 259–264. [Google Scholar] [PubMed]
  15. Bezerra, F.W.F.; Salazar, M.d.L.A.R.; Freitas, L.C.; de Oliveira, M.S.; dos Santos, I.R.C.; Dias, M.N.C.; Gomes-Leal, W.; Andrade, E.H.d.A.; Ferreira, G.C.; de Carvalho, R.N. Chemical Composition, Antioxidant Activity, Anti-Inflammatory and Neuroprotective Effect of Croton matourensis Aubl. Leaves Extracts Obtained by Supercritical CO2. J. Supercrit. Fluids 2020, 165, 104992. [Google Scholar] [CrossRef]
  16. Martins, A.O.B.P.B.; Rodrigues, L.B.; Cesário, F.R.A.S.; de Oliveira, M.R.C.; Tintino, C.D.M.; Castro, F.F.E.; Alcântara, I.S.; Fernandes, M.N.M.; de Albuquerque, T.R.; da Silva, M.S.A.; et al. Anti-Edematogenic and Anti-Inflammatory Activity of the Essential Oil from Croton rhamnifolioides Leaves and Its Major Constituent 1,8-Cineole (Eucalyptol). Biomed. Pharmacother. 2017, 96, 384–395. [Google Scholar] [CrossRef] [PubMed]
  17. Oliveira-Tintino, C.D.d.M.; Pessoa, R.T.; Fernandes, M.N.M.; Alcântara, I.S.; da Silva, B.A.F.; de Oliveira, M.R.C.; Martins, A.O.B.P.B.; da Silva, M.d.S.; Tintino, S.R.; Rodrigues, F.F.G.; et al. Anti-Inflammatory and Anti-Edematogenic Action of the Croton campestris A. St.-Hil (Euphorbiaceae) Essential Oil and the Compound β-Caryophyllene in in Vivo Models. Phytomedicine 2018, 41, 82–95. [Google Scholar] [CrossRef]
  18. Gupta, D.; Bleakley, B.; Gupta, R.K. Dragon’s Blood: Botany, Chemistry and Therapeutic Uses. J. Ethnopharmacol. 2007, 115, 361–380. [Google Scholar] [CrossRef]
  19. Block, S.; Stévigny, C.; De Pauw-Gillet, M.C.; de Hoffmann, E.; Llabrès, G.; Adjakidjé, V.; Quetin-Leclercq, J. Ent-Trachyloban-3β-Ol, a New Cytotoxic Diterpene from Croton zambesicus. Planta Med. 2002, 68, 647–649. [Google Scholar] [CrossRef]
  20. Ngamrojnavanich, N.; Sirimongkon, S.; Roengsumran, S.; Petsom, A.; Kamimura, H. Inhibition of Na+,K+-ATPase Activity by (-)-Ent-Kaur-16-En-19-Oic Acid and Its Derivatives. Planta Med. 2003, 69, 555–556. [Google Scholar] [CrossRef]
  21. Pierre-Ruphin, F.; Baholy, R.; Sylver, S.; Aubin Yves Oscar, R.; Mahamoud, A.; Francois Raymond, F.; Marcelin, S.; Jeannelle Rakotoniriana, H.; Amélie, R.; Koto-te-Nyiwa Ngbolua, K. GC-FID and GC/MS Analyses and Antimicrobial Activity of Croton greveanus, C. borarium and C. geayi (Euphorbiaceae) Essential Oils from Madagascar. J. Pharmacogn. Phytochem. 2016, 5, 188–197. [Google Scholar]
  22. Vigor, C.; Fabre, N.; Fourasté, I.; Moulis, C. Three Clerodane Diterpenoids from Croton eluteria Bennett. Phytochemistry 2001, 57, 1209–1212. [Google Scholar] [CrossRef] [PubMed]
  23. García-Díaz, J.; Tuenter, E.; Escalona-Arranz, J.C.; Llauradó Maury, G.; Cos, P.; Pieters, L. Antimicrobial Activity of Leaf Extracts and Isolated Constituents of Croton linearis. J. Ethnopharmacol. 2019, 236, 250–257. [Google Scholar] [CrossRef] [PubMed]
  24. Okokon, J.E.; Nwafor, P.A. Antimicrobial Activity of Root Extract and Crude Fractions of Croton zambesicus. Pak. J. Pharm. Sci. 2010, 23, 114–118. [Google Scholar] [PubMed]
  25. Panda, S.K.; Dutta, S.K.; Bastia, A.K. Antibacterial Activity of Croton roxburghii Balak. against the Enteric Pathogens. J. Adv. Pharm. Technol. Res. 2010, 1, 419–422. [Google Scholar] [CrossRef]
  26. Sá Firmino, N.C.; Alexandre, F.S.O.; de Vasconcelos, M.A.; Pinheiro, A.A.; Arruda, F.V.S.; Guedes, M.L.S.; Silveira, E.R.; Teixeira, E.H. Diterpenes Isolated from Croton blanchetianus Baill: Potential Compounds in Prevention and Control of the Oral Streptococci Biofilms. Ind. Crops Prod. 2019, 131, 371–377. [Google Scholar] [CrossRef]
  27. Ahmed, B.; Alam, T.; Varshney, M.; Khan, A. Hepatoprotective Activity of Two Plants Belonging to the Apiaceae and the Euphorbiaceae Family. J. Ethnopharmacol. 2002, 79, 313–316. [Google Scholar] [CrossRef] [PubMed]
  28. Grassi-Kassisse, D.M.; Wolf-Nunes, V.; Miotto, A.M.; Farias-Silva, E.; Brito, A.R.M.S.; Nunes, D.S.; Spadari-Bratfisch, R.C. Sensitivity to β-Adrenoceptor Agonists of Adipocytes from Rats Treated with an Aqueous Extract of Croton cajucara Benth. J. Pharm. Pharmacol. 2010, 55, 253–257. [Google Scholar] [CrossRef]
  29. Ravanelli, N.; Santos, K.P.; Motta, L.B.; Lago, J.H.G.; Furlan, C.M. Alkaloids from Croton echinocarpus Baill.: Anti-HIV Potential. S. Afr. J. Bot. 2016, 102, 153–156. [Google Scholar] [CrossRef]
  30. Terefe, E.M.; Okalebo, F.A.; Derese, S.; Muriuki, J.; Batiha, G.E.S. In Vitro Cytotoxicity and Anti-HIV Activity of Crude Extracts of Croton macrostachyus, Croton megalocarpus and Croton dichogamus. J. Exp. Pharmacol. 2021, 13, 971–979. [Google Scholar] [CrossRef]
  31. Mekonnen, A.N.; Asrade Atnafie, S.; Wahab Atta, M.A. Evaluation of Antiulcer Activity of 80% Methanol Extract and Solvent Fractions of the Root of Croton macrostachyus Hocsht: Ex Del. (Euphorbiaceae) in Rodents. Evid.-Based Complement. Altern. Med. 2020, 2020, 2809270. [Google Scholar] [CrossRef]
  32. Okokon, J.E.; Nwafor, P.A. Antiulcer and Anticonvulsant Activity of Croton Zambesicus. Pak. J. Pharm. Sci. 2009, 22, 384–390. [Google Scholar] [PubMed]
  33. Vidal, C.S.; Oliveira Brito Pereira Bezerra Martins, A.; de Alencar Silva, A.; de Oliveira, M.R.C.; Ribeiro-Filho, J.; de Albuquerque, T.R.; Coutinho, H.D.M.; da Silva Almeida, J.R.G.; Quintans, L.J.; de Menezes, I.R.A. Gastroprotective Effect and Mechanism of Action of Croton rhamnifolioides Essential Oil in Mice. Biomed. Pharmacother. 2017, 89, 47–55. [Google Scholar] [CrossRef] [PubMed]
  34. Kundu, A.; Dey, P.; Sarkar, P.; Karmakar, S.; Tae, I.H.; Kim, K.S.; Park, J.H.; Lee, S.H.; Lee, B.M.; Renthlei, L.; et al. Protective Effects of Croton hookeri on Streptozotocin-Induced Diabetic Nephropathy. Food Chem. Toxicol. 2020, 135, 110873. [Google Scholar] [CrossRef] [PubMed]
  35. Rodrigues, G.R.; Di Naso, F.C.; Porawski, M.; Marcolin, É.; Kretzmann, N.A.; Ferraz, A.D.B.F.; Richter, M.F.; Marroni, C.A.; Marroni, N.P. Treatment with Aqueous Extract from Croton cajucara Benth Reduces Hepatic Oxidative Stress in Streptozotocin-Diabetic Rats. J. Biomed. Biotechnol. 2012, 902351. [Google Scholar] [CrossRef] [PubMed]
  36. Torrico, F.; Cepeda, M.; Guerrero, G.; Melendez, F.; Blanco, Z.; Canelón, D.J.; Diaz, B.; Compagnone, R.S.; Suárez, A.I. Hypoglycaemic Effect of Croton cuneatus in Streptozotocin-Induced Diabetic Rats. Rev. Bras. Farmacogn. 2007, 17, 166–169. [Google Scholar] [CrossRef]
  37. Torrico, F.; Ramos, K.; Morales, A.; Guarirapa, L.; Cando, A.; Guerrero, G.; Márquez, G.; Compagnone, R.S.; Suárez, A.I. Evaluation of Acute Toxicity, Analgesic and Hipoglicaemic Activity of Aqueous Extract of Croton Pungens in Experimental Animals. Sci. J. Exp. Fac. Sci. 2013, 21, 181–191. [Google Scholar]
  38. Tufer, S.; Engidawork, E.; Ayele, A.G.; Bashea, C. Evaluation of the Diuretic Activity of Aqueous and 80% Methanol Extracts of Croton macrostachyus (Euphorbiaceae) Leaves in Saline-Loaded Rats. J. Exp. Pharmacol. 2021, 13, 213–221. [Google Scholar] [CrossRef]
  39. Guerrero, M.F.; Carrón, R.; Martín, M.L.; Román, L.S.; Reguero, M.T. Antihypertensive and Vasorelaxant Effects of Aqueous Extract from Croton Schiedeanus Schlecht in Rats. J. Ethnopharmacol. 2001, 5, 33–36. [Google Scholar] [CrossRef]
  40. Ortiz, A.P.; Puebla, P.; Guerrero, M.F. Vascular Interactions of Croton schiedeanus Major Flavonoids in Isolated Aortic Rings from Wistar Rats. Vitae 2021, 28, 343923. [Google Scholar] [CrossRef]
  41. Hort, M.A.; Straliotto, M.R.; Duz, M.S.; Netto, P.M.; Souza, C.B.; Schulz, T.; Horst, H.; Pizzolatti, M.G.; de Bem, A.F.; Ribeiro-do-Valle, R.M. Cardioprotective Effects of a Proanthocyanidin-Rich Fraction from Croton celtidifolius Baill: Focus on Atherosclerosis. Food Chem. Toxicol. 2012, 50, 3769–3775. [Google Scholar] [CrossRef]
  42. Peres, M.T.L.P.; Delle Monache, F.; Cruz, B.; Pizzolatti, M.G.; Yunes, R.A. Chemical Composition and Antimicrobial Activity of Croton urucurana Baillon (Euphorbiaceae). J. Ethnopharmacol. 1997, 56, 223–226. [Google Scholar] [CrossRef]
  43. Suárez, A.I.; Compagnone, R.S.; Salazar-Bookaman, M.M.; Tillett, S.; Delle Monache, F.; Di Giulio, C.; Bruges, G. Antinociceptive and Anti-Inflammatory Effects of Croton malambo Bark Aqueous Extract. J. Ethnopharmacol. 2003, 88, 11–14. [Google Scholar] [CrossRef] [PubMed]
  44. Ali Al-Hakami, I.; Raweh, S.; El-Shaibany, A.; Humaid, A.; Elaasser, M. A Review of Biological Activities of Genus Croton. PSM Microbiol. 2022, 7, 12–18. [Google Scholar]
  45. Guerra Júnior, J.I.; Ferreira, M.R.A.; de Oliveira, A.M.; Soares, L.A.L. Croton Sp.: A Review about Popular Uses, Biological Activities and Chemical Composition. Res. Soc. Dev. 2022, 11, e57311225306. [Google Scholar] [CrossRef]
  46. Moremi, M.P.; Makolo, F.; Viljoen, A.M.; Kamatou, G.P. A Review of Biological Activities and Phytochemistry of Six Ethnomedicinally Important South African Croton Species. J. Ethnopharmacol. 2021, 280, 114416. [Google Scholar] [PubMed]
  47. Huang, M.; Lu, J.-J.; Ding, J. Natural Products in Cancer Therapy: Past, Present and Future. Nat. Prod. Bioprospect. 2021, 11, 5–13. [Google Scholar] [CrossRef]
  48. Bailon-Moscoso, N.; Cevallos-Solorzano, G.; Romero-Benavides, J.; Ramirez Orellana, M. Natural Compounds as Modulators of Cell Cycle Arrest: Application for Anticancer Chemotherapies. Curr. Genom. 2017, 18, 106–131. [Google Scholar] [CrossRef]
  49. Maciel, M.A.M.; Pinto, A.C.; Arruda, A.C.; Pamplona, S.G.S.R.; Vanderlinde, F.A.; Lapa, A.J.; Echevarria, A.; Grynberg, N.F.; Côlus, I.M.S.; Farias, R.A.F.; et al. Ethnopharmacology, Phytochemistry and Pharmacology: A Successful Combination in the Study of Croton cajucara. J. Ethnopharmacol. 2000, 70, 41–55. [Google Scholar] [CrossRef]
  50. Galvão Freire, A.C.; Da Silva Melo, P.; Aoyama, H.; Haun, M.; Durán, N.; Ferreira, C.V. Cytotoxic Effect of the Diterpene Lactone Dehydrocrotonin from Croton cajucara on Human Promyelocytic Leukemia Cells. Planta Med. 2003, 69, 67–69. [Google Scholar] [CrossRef]
  51. Sandoval, M.; Okuhama, N.N.; Clark, M.; Angeles, F.M.; Lao, J.; Bustamante, S.; Miller, M.J.S. Sangre de Grado Croton palanostigma Induces Apoptosis in Human Gastrointestinal Cancer Cells. J. Ethnopharmacol. 2002, 80, 121–129. [Google Scholar] [CrossRef]
  52. Rossi, D.; Bruni, R.; Bianchi, N.; Chiarabelli, C.; Gambari, R.; Medici, A.; Lista, A.; Paganetto, G. Evaluation of the Mutagenic, Antimutagenic and Antiproliferative Potential of Croton lechleri (Muell. Arg.) Latex. Phytomedicine 2003, 10, 139–144. [Google Scholar] [CrossRef]
  53. Montopoli, M.; Bertin, R.; Chen, Z.; Bolcato, J.; Caparrotta, L.; Froldi, G. Croton Lechleri Sap and Isolated Alkaloid Taspine Exhibit Inhibition against Human Melanoma SK23 and Colon Cancer HT29 Cell Lines. J. Ethnopharmacol. 2012, 144, 747–753. [Google Scholar] [CrossRef] [PubMed]
  54. Fayad, W.; Fryknäs, M.; Brnjic, S.; Olofsson, M.H.; Larsson, R.; Linder, S. Identification of a Novel Topoisomerase Inhibitor Effective in Cells Overexpressing Drug Efflux Transporters. PLoS ONE 2009, 4, e7238. [Google Scholar] [CrossRef]
  55. Tzintzarov, A.; Boyadzhieva, S.S.; Coelho, J.A.P.; Tsvetanova, F.; Petrova, M.; Stoev, G.; Yankov, D.S.; Ugrinova, I.; Stateva, R.P. Novel Insights into the Biological Activity of Croton lechleri Twigs Extracts and Advancements in Their Sustainable Recovery. Molecules 2024, 29, 4161. [Google Scholar] [CrossRef] [PubMed]
  56. Block, S.; Gerkens, P.; Peulen, O.; Jolois, O.; Mingeot-Leclercq, M.P.; De Pauw-Gillet, M.C.; Quetin-Leclercq, J. Induction of Apoptosis in Human Promyelocytic Leukemia Cells by a Natural Trachylobane Diterpene. Anticancer Res. 2005, 25, 363–368. [Google Scholar]
  57. Kuo, P.C.; Shen, Y.C.; Yang, M.L.; Wang, S.H.; Tran, D.T.; Nguyen, X.D.; Chiang, P.C.; Lee, K.H.; Lee, E.J.; Wu, T.S. Crotonkinins A and B and Related Diterpenoids from Croton tonkinensis as Anti-Inflammatory and Antitumor Agents. J. Nat. Prod. 2007, 70, 1906–1909. [Google Scholar] [CrossRef]
  58. Lee, H.-M.; Kuo, P.-C.; Chen, W.-H.; Chen, P.-J.; Lam, S.-H.; Su, Y.-C.; Chen, C.-H. Diterpenoid from Croton tonkinensis as a Potential Radiation Sensitizer in Oral Squamous Cell Carcinoma: An In Vitro Study. Int. J. Mol. Sci. 2024, 25, 11839. [Google Scholar] [CrossRef]
  59. Pudhom, K.; Vilaivan, T.; Ngamrojanavanich, N.; Dechangvipart, S.; Sommit, D.; Petsom, A.; Roengsumran, S. Furanocembranoids from the Stem Bark of Croton oblongifolius. J. Nat. Prod. 2007, 70, 659–661. [Google Scholar] [CrossRef]
  60. Neiva, T.D.J.C.; De Moraes, A.C.R.; Buchele, C.; Pizzolatti, M.G.; D’Amico, E.A.; Fries, D.M.; Da Rocha, T.R.F. Antiplatelet Activity of Croton celditifolius. Rev. Bras. Cienc. Farm./Braz. J. Pharm. Sci. 2008, 44, 127–132. [Google Scholar] [CrossRef]
  61. Bezerra, D.P.; Marinho Filho, J.D.B.; Alves, A.P.N.N.; Pessoa, C.; De Moraes, M.O.; Pessoa, O.D.L.; Torres, M.C.M.; Silveira, E.R.; Viana, F.A.; Costa-Lotufo, L.V. Antitumor Activity of the Essential Oil from the Leaves of Croton regelianus and Its Component Ascaridole. Chem. Biodivers. 2009, 6, 1224–1231. [Google Scholar] [CrossRef]
  62. Santos, H.S.; Barros, F.W.A.; Albuquerque, M.R.J.R.; Bandeira, P.N.; Pessoa, C.; Braz-Filho, R.; Monte, F.J.Q.; Leal-Cardoso, J.H.; Lemos, T.L.G. Cytotoxic Diterpenoids from Croton argyrophylloides. J. Nat. Prod. 2009, 72, 1884–1887. [Google Scholar] [CrossRef]
  63. Rakotonandrasana, O.L.; Raharinjato, F.H.; Rajaonarivelo, M.; Dumontet, V.; Martin, M.T.; Bignon, J.; Rasoanaivo, P. Cytotoxic 3,4- Seco-Atisane Diterpenoids from Croton barorum and Croton goudotii. J. Nat. Prod. 2010, 73, 1730–1733. [Google Scholar] [CrossRef]
  64. Omosa, L.K.; Midiwo, J.O.; Masila, V.M.; Gisacho, B.M.; Munayi, R.; Francisca-Kamakama; Chemutai, K.P.; Elhaboob, G.; Saeed, M.E.M.; Hamdoun, S.; et al. Cytotoxicity of 91 Kenyan Indigenous Medicinal Plants towards Human CCRF-CEM Leukemia Cells. J. Ethnopharmacol. 2016, 179, 177–196. [Google Scholar] [CrossRef] [PubMed]
  65. Bhavana, J.; Kalaivani, M.K.; Sumathy, A. Cytotoxic and Pro-Apoptotic Activities of Leaf Extract of Croton bonplandianus Baill. against Lung Cancer Cell Line A549. Indian J. Exp. Biol. 2016, 54, 379–385. Available online: http://nopr.niscpr.res.in/handle/123456789/34322 (accessed on 30 June 2024).
  66. Suresh, M.; Alfonisan, M.; Alturaiki, W.; Al Aboody, M.S.; Alfaiz, F.A.; Premanathan, M.; Vijayakumar, R.; Umamagheswari, K.; Al Ghamdi, S.; Alsagaby, S.A. Investigations of Bioactivity of Acalypha indica (L.), Centella asiatica (L.) and Croton bonplandianus (Baill) against Multidrug Resistant Bacteria and Cancer Cells. J. Herb. Med. 2021, 28, 100359. [Google Scholar] [CrossRef]
  67. de Matos Cândido-Bacani, P.; Ezan, F.; de Oliveira Figueiredo, P.; Matos, M.d.F.C.; Rodrigues Garcez, F.; Silva Garcez, W.; Baffet, G. [1–9-NαC]-Crourorb A1 Isolated from Croton urucurana Latex Induces G2/M Cell Cycle Arrest and Apoptosis in Human Hepatocarcinoma Cells. Toxicol. Lett. 2017, 273, 44–54. [Google Scholar] [CrossRef]
  68. Mfotie Njoya, E.; Eloff, J.N.; McGaw, L.J. Croton Gratissimus Leaf Extracts Inhibit Cancer Cell Growth by Inducing Caspase 3/7 Activation with Additional Anti-Inflammatory and Antioxidant Activities. BMC Complement. Altern. Med. 2018, 18, 305. [Google Scholar] [CrossRef]
  69. Amaral, R.G.; Andrade, L.N.; Severino, P.; de Araújo, S.S.; Santos, M.I.S.; Dias, A.S.; de Moraes Filho, M.O.; Do O’Pessoa, C.; Carvalho, A.A.; Thomazzi, S.M. Investigation of the Possible Antioxidant and Anticancer Effects of Croton argyrophyllus (Euphorbiaceae). Chem. Eng. Trans. 2018, 64, 253–258. [Google Scholar] [CrossRef]
  70. Premprasert, C.; Yoenyongsawad, S.; Tewtrakul, S.; Wungsintaweeku, J. Plaunotol from Croton stellatopilosus Ohba Inhibited Cell Growth and Induced Apoptosis in Human Cancer Cell Lines. Songklanakarin J. Sci. Technol. 2019, 41, 846–855. [Google Scholar] [CrossRef]
  71. Wang, Y.; Tang, C.; Yao, S.; Lai, H.; Li, R.; Xu, J.; Wang, Q.; Fan, X.X.; Wu, Q.B.; Leung, E.L.H.; et al. Discovery of a Novel Protein Kinase C Activator from Croton tiglium for Inhibition of Non-Small Cell Lung Cancer. Phytomedicine 2019, 65, 153100. [Google Scholar] [CrossRef]
  72. Niu, Q.L.; Sun, H.; Liu, C.; Li, J.; Liang, C.X.; Zhang, R.R.; Ge, F.R.; Liu, W. Croton tiglium Essential Oil Compounds Have Anti-Proliferative and pro-Apoptotic Effects in A549 Lung Cancer Cell Lines. PLoS ONE 2020, 15, e0231437. [Google Scholar] [CrossRef]
  73. Liu, C.; Zhang, R.-R.; Wang, Y.-M.; Zhang, J.; Wang, Q.; Cheng, A.-W.; Guo, X.; Wang, X.-K.; Sun, J.-Y. Supercritical CO2 Fluid Extraction of Croton crassifolius Geisel Root: Chemical Composition and Anti-Proliferative, Autophagic, Apoptosis-Inducing, and Related Molecular Effects on A549 Tumour Cells. Phytomedicine 2019, 61, 152846. [Google Scholar] [CrossRef] [PubMed]
  74. Guo, X.; Zhang, R.R.; Sun, J.Y.; Liu, Y.; Yuan, X.S.; Chen, Y.Y.; Sun, H.; Liu, C. The Molecular Mechanism of Action for the Potent Antitumor Component Extracted Using Supercritical Fluid Extraction from Croton crassifolius Root. J. Ethnopharmacol. 2024, 327, 117835. [Google Scholar] [CrossRef] [PubMed]
  75. Cândido, A.C.S.; Scalon, S.P.Q.; Silva, C.B.; Simionatto, E.; Morel, A.F.; Stüker, C.Z.; Matos, M.F.C.; Peres, M.T.L.P. Chemical Composition and Phytotoxicity of Essential Oils of Croton doctoris S. Moore (Euphorbiaceae). Braz. J. Biol. 2021, 82, e231957. [Google Scholar] [CrossRef]
  76. Bhargav, E.; Salamma, S.; Chandana, B.; Harika, S.; Jyothi, M.V.; Rao, B.R.P. Bio Active Compound Analysis of Croton scabiosus Bedd: By HPTLC, GC-MS and Evaluation of Anthelmintic Activity and Anticancer Potential on Lung (A549) and Breast (MCF-7) Cancer Cell Lines. J. Pharm. Res. Int. 2021, 45–53. [Google Scholar] [CrossRef]
  77. Zhu, Q.; Li, Y.; Wang, C.; Yu, J.; Yue, J.; Zhou, B. Cytotoxic Diterpenoids from Croton kongensis Inhibiting Tumor Proliferation and Migration. Bioorg. Chem. 2024, 152, 107739. [Google Scholar] [CrossRef] [PubMed]
  78. Sánchez-Martínez, C.; Lallena, M.J.; Sanfeliciano, S.G.; de Dios, A. Cyclin Dependent Kinase (CDK) Inhibitors as Anticancer Drugs: Recent Advances (2015–2019). Bioorg. Med. Chem. Lett. 2019, 29, 126637. [Google Scholar] [CrossRef]
  79. Vermeulen, K.; Van Bockstaele, D.R.; Berneman, Z.N. The Cell Cycle: A Review of Regulation, Deregulation and Therapeutic Targets in Cancer. Cell Prolif. 2003, 36, 131–149. [Google Scholar] [CrossRef]
  80. Dickson, M.A.; Schwartz, G.K. Development of Cell-Cycle Inhibitors for Cancer Therapy. Curr. Oncol. 2009, 16, 36–43. [Google Scholar] [CrossRef]
  81. Qie, S.; Diehl, J.A. Cyclin D1, Cancer Progression, and Opportunities in Cancer Treatment. J. Mol. Med. 2016, 94, 1313–1326. [Google Scholar] [CrossRef]
  82. Cooke, M.; Magimaidas, A.; Casado-Medrano, V.; Kazanietz, M.G. Protein Kinase C in Cancer: The Top Five Unanswered Questions. Mol. Carcinog. 2017, 56, 1531–1542. [Google Scholar] [CrossRef]
  83. Poli, A.; Ramazzotti, G.; Matteucci, A.; Manzoli, L.; Lonetti, A.; Suh, P.G.; McCubrey, J.A.; Cocco, L. A Novel DAG-Dependent Mechanism Links PKCa and Cyclin B1 Regulating Cell Cycle Progression. Oncotarget 2014, 5, 11526–11540. [Google Scholar] [CrossRef] [PubMed]
  84. Canedo-Téxon, A.; Ramón-Farias, F.; Monribot-Villanueva, J.L.; Villafán, E.; Alonso-Sánchez, A.; Pérez-Torres, C.A.; Ángeles, G.; Guerrero-Analco, J.A.; Ibarra-Laclette, E. Novel Findings to the Biosynthetic Pathway of Magnoflorine and Taspine through Transcriptomic and Metabolomic Analysis of Croton draco (Euphorbiaceae). BMC Plant Biol. 2019, 19, 560. [Google Scholar] [CrossRef]
  85. Milanowski, D.J.; Winter, R.E.K.; Elvin-Lewis, M.P.F.; Lewis, W.H. Geographic Distribution of Three Alkaloid Chemotypes of Croton lechleri. J. Nat. Prod. 2002, 65, 814–819. [Google Scholar] [CrossRef]
  86. Zhang, Y.; Jiang, Q.; Wang, N.; Dai, B.; Chen, Y.; He, L. Effects of Taspine on Proliferation and Apoptosis by Regulating Caspase-3 Expression and the Ratio of BAX/BCL-2 in A431 Cells. Phytother. Res. 2011, 25, 357–364. [Google Scholar] [CrossRef]
  87. Kontro, M.; Kumar, A.; Majumder, M.; Eldfors, S.; Parsons, A.; Pemovska, T.; Saarela, J.; Yadav, B.; Malani, D.; Fløisand, Y.; et al. HOX Gene Expression Predicts Response to BCL-2 Inhibition in Acute Myeloid Leukemia. Leukemia 2017, 31, 301–309. [Google Scholar] [CrossRef] [PubMed]
  88. Zhu, M.; Yang, L.; Shi, X.; Gong, Z.; Yu, R.; Zhang, D.; Zhang, Y.; Ma, W. TPD7 Inhibits the Growth of Cutaneous T Cell Lymphoma H9 Cell through Regulating IL-2R Signalling Pathway. J. Cell. Mol. Med. 2019, 24, 984–995. [Google Scholar] [CrossRef]
  89. Belletti, B.; Nicoloso, M.S.; Schiappacassi, M.; Berton, S.; Lovat, F.; Wolf, K.; Canzonieri, V.; D’Andrea, S.; Zucchetto, A.; Friedl, P.; et al. Stathmin Activity Influences Sarcoma Cell Shape, Motility, and Metastatic Potential. Mol. Biol. Cell 2008, 19, 2003–2013. [Google Scholar] [CrossRef]
  90. Cambray-Deakin, M.A.; Burgoyne, R.D. Acetylated and Detyrosinated Alpha-Tubulins are Co-localized in Stable Microtubules in Rat Meningeal Fibroblasts. Cell Motil. Cytoskelet. 1987, 8, 284–291. [Google Scholar] [CrossRef] [PubMed]
  91. Perdiz, D.; Mackeh, R.; Poüs, C.; Baillet, A. The Ins and Outs of Tubulin Acetylation: More Than Just a Post-Translational Modification? Cell. Signal. 2011, 23, 763–771. [Google Scholar] [CrossRef]
  92. Ong, P.S.; Wang, L.Z.; Dai, X.; Tseng, S.H.; Loo, S.J.; Sethi, G. Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives. Front. Pharmacol. 2016, 25, 395. [Google Scholar] [CrossRef]
  93. Hennessy, B.; Smith, D.; Ram, P.T.; Lu, Y.; Mills, G.B. Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nat. Rev. Drug Discov. 2005, 4, 988–1004. [Google Scholar] [CrossRef] [PubMed]
  94. Lee, J.H.; Kim, C.; Um, J.-Y.; Sethi, G.; Ahn, K.S. Casticin-Induced Inhibition of Cell Growth and Survival are Mediated through the Dual Modulation of Akt/mTOR Signaling Cascade. Cancers 2019, 11, 254. [Google Scholar] [CrossRef] [PubMed]
  95. Yu, C.C.; Hung, S.K.; Liao, H.F.; Lee, C.C.; Lin, H.Y.; Lai, H.C.; Li, S.C.; Ho, H.C.; Huang, H.B.; Su, Y.C. RAD001 Enhances the Radiosensitivity of SCC4 Oral Cancer Cells by Inducing Cell Cycle Arrest at the G2/M Checkpoint. Anticancer Res. 2014, 34, 2927–2935. [Google Scholar]
  96. Shamloo, B.; Usluer, S. P21 in Cancer Research. Cancers 2019, 11, 1178. [Google Scholar] [CrossRef] [PubMed]
  97. Lara-Gonzalez, P.; Westhorpe, F.G.; Taylor, S.S. The Spindle Assembly Checkpoint. Curr. Biol. 2012, 22, R966–R980. [Google Scholar] [CrossRef]
Metabolites 15 00216 g001
Figure 1. Some Croton species with ethnopharmacological studies associated with cell cycle regulators. (A) C. draco Schltdl var. draco tree growing in Mexico. In this species, secondary metabolite-rich latex can be extracted from (B) branches and (C) stems. (D) Sectional classification of Croton species with applications in cancer treatment.
Figure 1. Some Croton species with ethnopharmacological studies associated with cell cycle regulators. (A) C. draco Schltdl var. draco tree growing in Mexico. In this species, secondary metabolite-rich latex can be extracted from (B) branches and (C) stems. (D) Sectional classification of Croton species with applications in cancer treatment.
Metabolites 15 00216 g001
Metabolites 15 00216 g002
Figure 2. Traditional uses of and patents for Croton species worldwide. (A) Geographical distribution of scientific publications detailing ethnopharmacological applications by country. (B) Summary of cancer cell lines reported in Croton antiproliferative assays. (C) Patents protecting biotechnological and pharmacological uses of Croton species reported in the last 61 years. Diagrams created with BioRender.
Figure 2. Traditional uses of and patents for Croton species worldwide. (A) Geographical distribution of scientific publications detailing ethnopharmacological applications by country. (B) Summary of cancer cell lines reported in Croton antiproliferative assays. (C) Patents protecting biotechnological and pharmacological uses of Croton species reported in the last 61 years. Diagrams created with BioRender.
Metabolites 15 00216 g002
Metabolites 15 00216 g003
Figure 3. Chemical structures of SMs with reported cell cycle-related targets that have been identified in Croton species: (1) Trans-dehidrocrotonin, (2) Trans-crotonin, (3) Ent-trachyloban-3,-ol, (4) Crotonquinin A, (5) Crotonquinin B, (6–9) Furanocembranoids 1-4, (10) Catechin, (11) Galocatechin, (12) Ascaridol, (13) Taspine, (14–16) Ent-kaurene 1-3, (17) Rutin, (18) Vitexin, (19) Crourorb A1, (20) Crotobarin, (21) Crotogoudin, (22) B10G5, (23) Plaunotol, (24) Ent-kaurane I, (25) NCKU_PCKuo_0001, and (26) Chettaphanin II.
Figure 3. Chemical structures of SMs with reported cell cycle-related targets that have been identified in Croton species: (1) Trans-dehidrocrotonin, (2) Trans-crotonin, (3) Ent-trachyloban-3,-ol, (4) Crotonquinin A, (5) Crotonquinin B, (6–9) Furanocembranoids 1-4, (10) Catechin, (11) Galocatechin, (12) Ascaridol, (13) Taspine, (14–16) Ent-kaurene 1-3, (17) Rutin, (18) Vitexin, (19) Crourorb A1, (20) Crotobarin, (21) Crotogoudin, (22) B10G5, (23) Plaunotol, (24) Ent-kaurane I, (25) NCKU_PCKuo_0001, and (26) Chettaphanin II.
Metabolites 15 00216 g003
Metabolites 15 00216 g004
Figure 4. Schematic representation of cell cycle control by natural compounds from the Croton genus. Progression through the cell cycle involves the formation, activation, and successive participation of cyclin-dependent protein kinases (CDKs), which bind sequentially to a series of cyclins and regulate the cell cycle at different stages. Crude extracts and natural compounds isolated from the Croton genus, e.g., taspine, plaunotol, B10G5, chettaphanin II, NCKU_PCK_000, and ent-kaurane-I, have been shown to influence specific targets at different points, altering cell cycle progression through inhibition of CDK–cyclin complexes and overexpression of apoptosis mediators. In addition to cell cycle arrest induction, upstream signaling routes that sense DNA damage and trigger cell death programs via gene expression modulation have also been linked to Croton extracts such as CCEO, CTEO, TPD7, and crourorbA1. Diagram created with BioRender.
Figure 4. Schematic representation of cell cycle control by natural compounds from the Croton genus. Progression through the cell cycle involves the formation, activation, and successive participation of cyclin-dependent protein kinases (CDKs), which bind sequentially to a series of cyclins and regulate the cell cycle at different stages. Crude extracts and natural compounds isolated from the Croton genus, e.g., taspine, plaunotol, B10G5, chettaphanin II, NCKU_PCK_000, and ent-kaurane-I, have been shown to influence specific targets at different points, altering cell cycle progression through inhibition of CDK–cyclin complexes and overexpression of apoptosis mediators. In addition to cell cycle arrest induction, upstream signaling routes that sense DNA damage and trigger cell death programs via gene expression modulation have also been linked to Croton extracts such as CCEO, CTEO, TPD7, and crourorbA1. Diagram created with BioRender.
Metabolites 15 00216 g004
Table 1. Compounds in the Croton genus that are involved in cell cycle processes and apoptosis. The extraction methods, doses, and experimental models are indicated.
Table 1. Compounds in the Croton genus that are involved in cell cycle processes and apoptosis. The extraction methods, doses, and experimental models are indicated.
SpeciesMolecule/Extraction Method/DoseStudy ModelBiological Activity/Target RegulationRef.
C. cajucaraDCTN and CTN/Hexane and Methanol/80 and 120 mg/KgSarcoma-180 cells and
Ehrlich carcinoma		Tumor inhibition, TNF-α[49]
t-DCTN/-/180 µMHL-60 cellsCytotoxic activity[50]
C. palanostigmaLatex/Aqueous extract/100 µL/mLHT-29, and HT-84 cellsApoptosis, β-tubulin[51]
C. lechleriLatex/DMSO/2.5 µg/mLK562 cellsCellular proliferation inhibition[52]
Latex and taspine/Dichloromethane–Methanol/1 to 10 µg/mLSK23 cellsApoptotic activity
α-tubulin, F-actin		[53]
Taspine/-/10 mg/KgHCT-116 modelApoptosis in vivo, Topoisomerase I, and II inhibitor[54]
Rutin and vitexin/Methanol/17 µg/mLHeLa, SW-480, and MDAMB-231 cellsApoptotic activity[7]
Twig extracts/Soxhlet ethanol and pressurized ethanol/13.31 to 249.8 µg/mLHaCat and A375 cellsApoptotic activity
Cell cycle arrest		[55]
C. zambesicusEnt-18 hidroxy-traquilobano-3β-ol/Dichloromethane extract/7.3 µg/mLHeLa and HL-60 cellsCaspase-3/CPP32[56]
C. tonkinensisCrotonkinins A-B/Methanolic extract/0.61 to 1.45 µg/mLMCF-7, A549, and KB cellsCellular proliferation inhibition[57]
NCKU_PCKuo_0001/-/10 µMHNSCC cell lineCell viability and AKT/mTOR downregulation[58]
C. oblongifoliusFuranocembranoids/Hexane fraction/5.6 to 9.5 µ g/mLBT474, HEP-G2, Kato-3, and SW-620 cellsCytotoxic activity[59]
C. celtidifoliusCatequin and gallocatequin/Aqueous ethanol extract/200 µg/mLHuman plateletsPlatelet aggregation inhibition[60]
C. regelianusAscaridole and essential oils/Hidrodistilled extract/6.3 to 18.4 µg/mLHL-60, SF-295, and HCT-8 cellsCytotoxic activity[61]
C. argyrophylloidesEnt-kaurene 1-3/Ethanol extract/1.5 to 8.2 µg/mL HL-60, MDAMB-435, SF-295, and HCT-8 cellsCytotoxic activity [62]
C. barorumCrotobarin and crotogoudin/Ethyl acetate extract/4 µMMurine P388 cellsCytotoxic activity
Cell cycle arrest (G2/M)		[63]
C. sylvaticusRoot bark/Dichloromethane–Methanol/10 µg/mL CCRF-CEM cellsCytotoxic activity[64]
C. bonplandianusLeaf extract/Acetone extract/15.68 µg/mLA549 cellsCytotoxic and apoptotic activities[65]
Leaf extract/Ethanolic fraction/86.33 µg/mLK562 cellsCytotoxic activity[66]
C. urucuranaCrourorb A1/Ethyl acetate/35.75 µg/mLHuh-7 cellsCDK1, Cyclin B1, MAP Kinases
JNK signaling		[67]
C. gratissimusLeaf extracts/Acetone and ethanol/152.3 to 462.88 µg/mLHeLa CellsCytotoxic activity and Caspase-3 and -7 activation[68]
C. argyrophyllusEssential oil/Hydrodistilled extract/14.81 to 32.79 µg/mLMDAMB-435 and OVCAR cellsCytotoxic activity[69]
C. stellatopilosusPlaunotol/Hexane extract/65.47 to 80.90 µg/mLMCF7, KB, HeLa, and HT-29 cellsTNF-α, BCL-2, BAK/BAX[70]
C. tigliumB10G5/-/0.11 to 20 µMA549 and H1975 cellsPKC activation, Cyclin B1, Cyclin D1, PARP[71]
CTEO/Supercritical CO2 fluid extract/48.38 µg/mLA549 cellsProliferation inhibition, cell cycle arrest. Cyclin and CDK inhibition.[72]
C. crassifoliusCCEO/Supercritical CO2 fluid extract/25 µg/mLA549 cellsApoptosis, Cyclin B1, Cyclin A, CDK1[73]
Chettaphanin II/Supercritical CO2 fluid extract/8.58 µMA549 cellsBAX, BCL-2, Cyt-C,
Cell cycle arrest, mTOR/PI3K/Akt signaling		[74]
C. doctorisEssential oils/Hexane fraction/13.4–21.8 µg/mLUACC62 and OVCAR cellsCytotoxic activity[75]
C. scabiosusBark extracts/Chloroform and ethyl acetate/187.33 to 201.89 µg/mL A549 and MCF7 cellsCytotoxic activity[76]
C. kongensisEnt-kaurane I/Ethyl acetate extract/1 to 4 µMMDA-MB-231 cellsApoptotic activity and regulation of STAT3 and FAK signal pathways[77]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Alamillo-Vásquez, J.A.; Pérez-Torres, C.-A.; Ibarra-Laclette, E.; Ramón-Farías, F.; Nicasio-Torres, P.; Alatorre-Cobos, F. Secondary Metabolites from Croton Species and Their Biological Activity on Cell Cycle Regulators. Metabolites 2025, 15, 216. https://doi.org/10.3390/metabo15040216

AMA Style

Alamillo-Vásquez JA, Pérez-Torres C-A, Ibarra-Laclette E, Ramón-Farías F, Nicasio-Torres P, Alatorre-Cobos F. Secondary Metabolites from Croton Species and Their Biological Activity on Cell Cycle Regulators. Metabolites. 2025; 15(4):216. https://doi.org/10.3390/metabo15040216

Chicago/Turabian Style

Alamillo-Vásquez, Jorge Augusto, Claudia-Anahí Pérez-Torres, Enrique Ibarra-Laclette, Feliza Ramón-Farías, Pilar Nicasio-Torres, and Fulgencio Alatorre-Cobos. 2025. "Secondary Metabolites from Croton Species and Their Biological Activity on Cell Cycle Regulators" Metabolites 15, no. 4: 216. https://doi.org/10.3390/metabo15040216

APA Style

Alamillo-Vásquez, J. A., Pérez-Torres, C.-A., Ibarra-Laclette, E., Ramón-Farías, F., Nicasio-Torres, P., & Alatorre-Cobos, F. (2025). Secondary Metabolites from Croton Species and Their Biological Activity on Cell Cycle Regulators. Metabolites, 15(4), 216. https://doi.org/10.3390/metabo15040216

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop