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Cancer Cell Models for the Development of Anti-cancer Drugs

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 39037

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Special Issue Editor

Dr. Nitin Telang

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Guest Editor

Cancer Prevention Research Program, Palindrome Liaisons Consultants, Montvale, NJ 07645-1559, USA
Interests: preclinical oncology; cellular models for breast and colon cancer; cancer stem cell biology; lead compound efficacy

Special Issue Information

Dear Colleagues,

The epithelial organ site cancers are profoundly influenced by environmental, dietary and life style factors during the multi-step process of initiation, promotion and progression. Tissue culture systems that utilize organ culture, cell culture, ex-vivo models for patient-derived xenografts (PDX) and for patient derived organoids (PDO) facilitate mechanistic studies on cancer development and cancer therapy. Conventional chemo-endocrine therapy or molecularly targeted therapy is frequently associated with systemic toxicity, spontaneous or acquired tumor resistance and emergence of therapy-resistant stem cell population that favor progression to advanced stage metastatic cancer. These limitations underscore an unmet need to develop efficacious less toxic and more selective anti-cancer drugs. The cancer cell culture models may provide valuable mechanism-driven approaches for initial screening and prioritizing promising new anti-cancer drugs as clinically translatable lead compounds.

This special issue welcomes research articles and reviews focusing on new experimental directions that utilize tumor organ and cell culture, cancer stem cell culture, and ex-vivo PDX and PDO models for their diagnostic or therapeutic applications.

Dr. Nitin Telang
Guest Editor

Manuscript Submission Information

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Keywords

Tumor organ culture and cell culture
Cancer stem cell models
Patient derived xenograft (PDX) and patient derived organoid (PDO) models
Biomarker end points
Mechanistic pathways
Molecular targets
New anti-cancer agents

Published Papers (11 papers)

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Editorial

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2 pages, 162 KiB

Open AccessEditorial

Cancer Cell Models for the Development of Anti-Cancer Drugs

by Nitin T. Telang

Int. J. Mol. Sci. 2022, 23(22), 14457; https://doi.org/10.3390/ijms232214457 - 21 Nov 2022

Viewed by 972

Abstract

In the multi-factorial etiology of organ-site cancers by suspect human chemical carcinogens, oncogenic virus, activation of RAS, Myc and HER-2 oncogenes, inactivation of TP53, RB and APC tumor suppressor genes represent early-occurring genetic events [...] Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

Research

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25 pages, 5288 KiB

Open AccessArticle

Characterisation of 3D Bioprinted Human Breast Cancer Model for In Vitro Drug and Metabolic Targeting

by Titanilla Dankó, Gábor Petővári, Regina Raffay, Dániel Sztankovics, Dorottya Moldvai, Enikő Vetlényi, Ildikó Krencz, András Rókusz, Krisztina Sipos, Tamás Visnovitz, Judit Pápay and Anna Sebestyén

Int. J. Mol. Sci. 2022, 23(13), 7444; https://doi.org/10.3390/ijms23137444 - 4 Jul 2022

Cited by 9 | Viewed by 3184

Abstract

Monolayer cultures, the less standard three-dimensional (3D) culturing systems, and xenografts are the main tools used in current basic and drug development studies of cancer research. The aim of biofabrication is to design and construct a more representative in vivo 3D environment, replacing two-dimensional (2D) cell cultures. Here, we aim to provide a complex comparative analysis of 2D and 3D spheroid culturing, and 3D bioprinted and xenografted breast cancer models. We established a protocol to produce alginate-based hydrogel bioink for 3D bioprinting and the long-term culturing of tumour cells in vitro. Cell proliferation and tumourigenicity were assessed with various tests. Additionally, the results of rapamycin, doxycycline and doxorubicin monotreatments and combinations were also compared. The sensitivity and protein expression profile of 3D bioprinted tissue-mimetic scaffolds showed the highest similarity to the less drug-sensitive xenograft models. Several metabolic protein expressions were examined, and the in situ tissue heterogeneity representing the characteristics of human breast cancers was also verified in 3D bioprinted and cultured tissue-mimetic structures. Our results provide additional steps in the direction of representing in vivo 3D situations in in vitro studies. Future use of these models could help to reduce the number of animal experiments and increase the success rate of clinical phase trials. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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16 pages, 13655 KiB

Open AccessArticle

Potential Chemotherapeutic Effect of Selenium for Improved Canceration of Esophageal Cancer

by Anil Ahsan, Zhiwei Liu, Ruibing Su, Chencai Liu, Xiaoqi Liao and Min Su

Int. J. Mol. Sci. 2022, 23(10), 5509; https://doi.org/10.3390/ijms23105509 - 14 May 2022

Cited by 11 | Viewed by 2316

Abstract

Esophageal squamous cell carcinoma is the most common type of esophageal cancer and accounts for 5% of malignant tumor deaths. Recent research suggests that chronic inflammation and DNA damage may drive the onset of esophageal squamous cell carcinoma, implying that lowering chronic inflammation and DNA damage compounds may provide chemo-prevention. According to epidemiological and experimental evidence, selenium is linked to a lower risk of several malignancies, including esophageal squamous cell carcinoma. However, its exact mechanism is still unclear. In the present study, we used cell lines and a 4-NQO mice model to explore the anti-cancer mechanism of four types of selenium. Our findings indicated that selenium inhibited the proliferation, colony formation, and ROS level of ESCC cell lines in a time-dependent manner. Intriguingly, selenium treatment impeded 4-NQO-induced high-grade intraepithelial neoplasia and reduced the number of positive inflammatory cells by preserving DNA from oxidative damage. In addition, selenium significantly decreased the expression of Ki-67 and induced apoptosis. This study demonstrates that selenium has a significant chemo-preventive effect on ESCC by reducing high-grade dysplasia to low-grade dysplasia. For the first time, selenium was shown to slow down the progression of esophageal cancer by lowering inflammation and oxidative DNA damage. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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12 pages, 2332 KiB

Open AccessArticle

INSIDIA 2.0 High-Throughput Analysis of 3D Cancer Models: Multiparametric Quantification of Graphene Quantum Dots Photothermal Therapy for Glioblastoma and Pancreatic Cancer

by Giordano Perini, Enrico Rosa, Ginevra Friggeri, Lorena Di Pietro, Marta Barba, Ornella Parolini, Gabriele Ciasca, Chiara Moriconi, Massimiliano Papi, Marco De Spirito and Valentina Palmieri

Int. J. Mol. Sci. 2022, 23(6), 3217; https://doi.org/10.3390/ijms23063217 - 16 Mar 2022

Cited by 10 | Viewed by 2780

Abstract

Cancer spheroids are in vitro 3D models that became crucial in nanomaterials science thanks to the possibility of performing high throughput screening of nanoparticles and combined nanoparticle-drug therapies on in vitro models. However, most of the current spheroid analysis methods involve manual steps. This is a time-consuming process and is extremely liable to the variability of individual operators. For this reason, rapid, user-friendly, ready-to-use, high-throughput image analysis software is necessary. In this work, we report the INSIDIA 2.0 macro, which offers researchers high-throughput and high content quantitative analysis of in vitro 3D cancer cell spheroids and allows advanced parametrization of the expanding and invading cancer cellular mass. INSIDIA has been implemented to provide in-depth morphologic analysis and has been used for the analysis of the effect of graphene quantum dots photothermal therapy on glioblastoma (U87) and pancreatic cancer (PANC-1) spheroids. Thanks to INSIDIA 2.0 analysis, two types of effects have been observed: In U87 spheroids, death is accompanied by a decrease in area of the entire spheroid, with a decrease in entropy due to the generation of a high uniform density spheroid core. On the other hand, PANC-1 spheroids’ death caused by nanoparticle photothermal disruption is accompanied with an overall increase in area and entropy due to the progressive loss of integrity and increase in variability of spheroid texture. We have summarized these effects in a quantitative parameter of spheroid disruption demonstrating that INSIDIA 2.0 multiparametric analysis can be used to quantify cell death in a non-invasive, fast, and high-throughput fashion. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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16 pages, 2729 KiB

Open AccessArticle

Therapeutic Effect of Melittin–dKLA Targeting Tumor-Associated Macrophages in Melanoma

by Ik-Hwan Han, Chanmi Jeong, Juwon Yang, Seung-Hyeok Park, Deok-Sang Hwang and Hyunsu Bae

Int. J. Mol. Sci. 2022, 23(6), 3094; https://doi.org/10.3390/ijms23063094 - 13 Mar 2022

Cited by 7 | Viewed by 3457

Abstract

Melanoma is an immunogenic tumor and a serious type of skin cancer. Tumor-associated macrophages (TAMs) express an M2-like phenotype and are involved in all stages of melanomagenesis; it is hence a promising target for cancer immunotherapy. We herein investigated whether melittin–dKLA inhibits the growth of melanoma by inducing apoptosis of M2-like macrophages. For the in vitro study, a conditioned medium of macrophages was prepared from M0, M1, or M2-differentiated THP-1 cells with and without melittin–dKLA. The affinity of melittin for M2 macrophages was studied with FITC (fluorescein isothiocyanate)-conjugated melittin. For the in vivo study, murine melanoma cells were inoculated subcutaneously in the right flank of mice, melittin–dKLA was intraperitoneally injected at 200 nmol/kg every three days, and flow cytometry analysis of TAMs was performed. Since melittin binds preferentially to M2-like macrophages, melittin–dKLA induced more caspase 3 expression and cell death in M2 macrophages compared with M0 and M1 macrophages and melanoma cells. Melittin–dKLA significantly inhibited the proliferation and migration of M2 macrophages, resulting in a decrease in melanoma tumor growth in vivo. The CD206⁺ M2-like TAMs were reduced, while the CD86⁺ M1-like TAMs were not affected. Melittin–dKLA is therapeutically effective against melanoma by inducing the apoptosis of M2-like TAMs. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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18 pages, 4289 KiB

Open AccessArticle

Charge Conversion Polymer–Liposome Complexes to Overcome the Limitations of Cationic Liposomes in Mitochondrial-Targeting Drug Delivery

by Pei-Wei Shueng, Lu-Yi Yu, Hsiao-Hsin Hou, Hsin-Cheng Chiu and Chun-Liang Lo

Int. J. Mol. Sci. 2022, 23(6), 3080; https://doi.org/10.3390/ijms23063080 - 12 Mar 2022

Cited by 9 | Viewed by 3225

Abstract

Mitochondrial-targeting therapy is considered an important strategy for cancer treatment. (3-Carboxypropyl) triphenyl phosphonium (CTPP) is one of the candidate molecules that can drive drugs or nanomedicines to target mitochondria via electrostatic interactions. However, the mitochondrial-targeting effectiveness of CTPP is low. Therefore, pH-sensitive polymer–liposome complexes with charge-conversion copolymers and CTPP-containing cationic liposomes were designed for efficiently delivering an anti-cancer agent, ceramide, into cancer cellular mitochondria. The charge-conversion copolymers, methoxypoly(ethylene glycol)-block-poly(methacrylic acid-g-histidine), were anionic and helped in absorbing and shielding the positive charges of cationic liposomes at pH 7.4. In contrast, charge-conversion copolymers became neutral in order to depart from cationic liposomes and induced endosomal escape for releasing cationic liposomes into cytosol at acidic endosomes. The experimental results reveal that these pH-sensitive polymer–liposome complexes could rapidly escape from MCF-7 cell endosomes and target MCF-7 mitochondria within 3 h, thereby leading to the generation of reactive oxygen species and cell apoptosis. These findings provide a promising solution for cationic liposomes in cancer mitochondrial-targeting drug delivery. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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13 pages, 3216 KiB

Open AccessArticle

Functional Significance of Selective Expression of ERα and ERβ in Mammary Gland Organ Culture

by Rajendra G. Mehta

Int. J. Mol. Sci. 2021, 22(23), 13151; https://doi.org/10.3390/ijms222313151 - 5 Dec 2021

Cited by 3 | Viewed by 1578

Abstract

Thoracic pair of mammary glands from steroid hormone-pretreated mice respond to hormones structurally and functionally in organ culture. A short exposure of glands for 24 h to 7,12 Dimethylbenz(a)anthracene (DMBA) during a 24-day culture period induced alveolar or ductal lesions. Methods: To differentiate the functional significance of ERα and ERβ, we employed estrogen receptor (ER) knockout mice. We compared the effects of DMBA on the development of preneoplastic lesions in the glands in the absence of ERα (αERKO) and ERβ (βERKO) using an MMOC protocol. Glands were also subjected to microarray analyses. We showed that estradiol can be replaced by EGF for pretreatment of mice. The carcinogen-induced lesions developed under both steroids and EGF pretreatment protocols. The glands from αERKO did not develop any lesions, whereas in βERKO mice in which ERα is intact, mammary alveolar lesions developed. Comparison of microarrays of control, αERKO and βERKO mice showed that ERα was largely responsible for proliferation and the MAP kinase pathways, whereas ERβ regulated steroid metabolism-related genes. The results indicate that ERα is essential for the development of precancerous lesions. Both subtypes, ERα and Erβ, differentially regulated gene expression in mammary glands in organ cultures. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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20 pages, 4653 KiB

Open AccessArticle

Novel Dipyridinium Lipophile-Based Ionic Liquids Tethering Hydrazone Linkage: Design, Synthesis and Antitumorigenic Study

by Salsabeel Al-Sodies, Nadjet Rezki, Fawzia Faleh Albelwi, Mouslim Messali, Mohamed R. Aouad, Sanaa K. Bardaweel and Mohamed Hagar

Int. J. Mol. Sci. 2021, 22(19), 10487; https://doi.org/10.3390/ijms221910487 - 28 Sep 2021

Cited by 7 | Viewed by 1640

Abstract

Novel dicationic pyridinium ionic liquids tethering amphiphilic long alkyl side chains and fluorinated counter anions have been successfully synthesized by means of the quaternization of the dipyridinium hydrazone through its alkylation with different alkyl halides. The resulting halogenated di-ionic liquids underwent a metathesis reaction in order to incorporate some fluorinated counter anions in their structures. The structures of all the resulting di-ionic liquids were characterized by several spectroscopic experiments. The antitumorigenic activities of the investigated compounds were further studied against three different human lung cancer cell lines. Compared to the standard chemotherapeutic agent, cisplatin, the synthesized di-ionic liquids exerted equal, even more active, moderate, or weak anticancer activities against the various lung cancer cell lines under investigation. The observed anticancer activity appears to be enhanced by increasing the length of the aliphatic side chains. Moreover, dicationic pyridinium bearing a nine carbon chain as counter cation and hexafluoro phosphate and/or tetrafluoro bororate as counter anion were selected for further evaluation and demonstrated effective and significant antimetastatic effects and suppressed the colonization ability of the lung cancer cells, suggesting a therapeutic potential for the synthesized compounds in lung cancer treatment. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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Review

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31 pages, 3239 KiB

Open AccessReview

Current Advances in 3D Bioprinting for Cancer Modeling and Personalized Medicine

by Nicolas Germain, Melanie Dhayer, Salim Dekiouk and Philippe Marchetti

Int. J. Mol. Sci. 2022, 23(7), 3432; https://doi.org/10.3390/ijms23073432 - 22 Mar 2022

Cited by 34 | Viewed by 5549

Abstract

Tumor cells evolve in a complex and heterogeneous environment composed of different cell types and an extracellular matrix. Current 2D culture methods are very limited in their ability to mimic the cancer cell environment. In recent years, various 3D models of cancer cells have been developed, notably in the form of spheroids/organoids, using scaffold or cancer-on-chip devices. However, these models have the disadvantage of not being able to precisely control the organization of multiple cell types in complex architecture and are sometimes not very reproducible in their production, and this is especially true for spheroids. Three-dimensional bioprinting can produce complex, multi-cellular, and reproducible constructs in which the matrix composition and rigidity can be adapted locally or globally to the tumor model studied. For these reasons, 3D bioprinting seems to be the technique of choice to mimic the tumor microenvironment in vivo as closely as possible. In this review, we discuss different 3D-bioprinting technologies, including bioinks and crosslinkers that can be used for in vitro cancer models and the techniques used to study cells grown in hydrogels; finally, we provide some applications of bioprinted cancer models. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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18 pages, 643 KiB

Open AccessReview

Preclinical Evaluation of CAR T Cell Function: In Vitro and In Vivo Models

by Xiaohui Si, Lu Xiao, Christine E. Brown and Dongrui Wang

Int. J. Mol. Sci. 2022, 23(6), 3154; https://doi.org/10.3390/ijms23063154 - 15 Mar 2022

Cited by 12 | Viewed by 9808

Abstract

Immunotherapy using chimeric antigen receptor (CAR) T cells is a rapidly emerging modality that engineers T cells to redirect tumor-specific cytotoxicity. CAR T cells have been well characterized for their efficacy against B cell malignancies, and rigorously studied in other types of tumors. Preclinical evaluation of CAR T cell function, including direct tumor killing, cytokine production, and memory responses, is crucial to the development and optimization of CAR T cell therapies. Such comprehensive examinations are usually performed in different types of models. Model establishment should focus on key challenges in the clinical setting and the capability to generate reliable data to indicate CAR T cell therapeutic potency in the clinic. Further, modeling the interaction between CAR T cells and tumor microenvironment provides additional insight for the future endeavors to enhance efficacy, especially against solid tumors. This review will summarize both in vitro and in vivo models for CAR T cell functional evaluation, including how they have evolved with the needs of CAR T cell research, the information they can provide for preclinical assessment of CAR T cell products, and recent technology advances to test CAR T cells in more clinically relevant models. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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13 pages, 1302 KiB

Open AccessReview

Drug-Resistant Stem Cells: Novel Approach for Colon Cancer Therapy

by Nitin Telang

Int. J. Mol. Sci. 2022, 23(5), 2519; https://doi.org/10.3390/ijms23052519 - 24 Feb 2022

Cited by 8 | Viewed by 3132

Abstract

Background: Next to breast cancer, advanced stage metastatic colon cancer represents a major cause for mortality in women. Germline or somatic mutations in tumor suppressor genes or in DNA mismatch repair genes represent risk factors for genetic predisposition of colon cancer that are also detectable in sporadic colon cancer. Conventional chemotherapy for colon cancer includes combination of 5-fluoro-uracil with oxaliplatin and irinotecan or targeted therapy with non-steroid anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors. Major limitations of these therapeutic interventions are associated with systemic toxicity, acquired tumor resistance and the emergence of drug resistant stem cells that favor initiation, progression and metastasis of therapy-resistant disease. These limitations emphasize an unmet need to identify tumor stem cell selective testable alternatives. Drug-resistant stem cell models facilitate the identification of new testable alternatives from natural phytochemicals and herbal formulations. The goal of this review is to provide an overview relevant to the current status of conventional/targeted therapy, the role of cancer stem cells and the status of testable alternatives for therapy-resistant colon cancer. Experimental models: Hyper-proliferative and tumorigenic cell lines from genetically predisposed colonic tissues of female mice represent experimental models. Chemotherapeutic agents select drug-resistant phenotypes that exhibit upregulated expressions of cellular and molecular stem cell markers. Mechanistically distinct natural phytochemicals effectively inhibit stem cell growth and downregulate the expressions of stem cell markers. Conclusions: The present review discusses the status of colon cancer therapy and inherent limitations, cancer stem cell biology, potential lead compounds and their advantages over chemotherapy. The present experimental approaches will facilitate the identification of pharmacological and naturally-occurring agents as lead compounds for stem cell targeted therapy of colon cancer. Full article

(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)

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