International Journal of Molecular Sciences

Research

17 pages, 3404 KiB

Open AccessArticle

Synthesis of Novel 2-(Cyclopentylamino)thiazol-4(5H)-one Derivatives with Potential Anticancer, Antioxidant, and 11β-HSD Inhibitory Activities

by Szymon Baumgart, Daria Kupczyk, Aneta Archała, Oliwia Koszła, Przemysław Sołek, Wojciech Płaziński, Anita Płazińska and Renata Studzińska

Int. J. Mol. Sci. 2023, 24(8), 7252; https://doi.org/10.3390/ijms24087252 - 14 Apr 2023

Cited by 6 | Viewed by 2004

Abstract

In this study, a series of nine new 2-(cyclopentylamino)thiazol-4(5H)-one derivatives were synthesized, and their anticancer, antioxidant, and 11β-hydroxysteroid dehydrogenase (11β-HSD) inhibitory activities were tested. Anticancer activity has been assessed using the MTS (MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay against human colon carcinoma (Caco-2), human [...] Read more.

In this study, a series of nine new 2-(cyclopentylamino)thiazol-4(5H)-one derivatives were synthesized, and their anticancer, antioxidant, and 11β-hydroxysteroid dehydrogenase (11β-HSD) inhibitory activities were tested. Anticancer activity has been assessed using the MTS (MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay against human colon carcinoma (Caco-2), human pancreatic carcinoma (PANC-1), glioma (U-118 MG), human breast carcinoma (MDA-MB-231), and skin melanoma (SK-MEL-30) cancer cell lines. Cell viability reductions, especially in the case of Caco-2, MDA-MB-231, and SK-MEL-30 lines, were observed for most compounds. In addition, the redox status was investigated and oxidative, but nitrosative stress was not noted at a concentration of 500 µM compounds tested. At the same time, a low level of reduced glutathione was observed in all cell lines when treated with compound 3g (5-(4-bromophenyl)-2-(cyclopentylamino)thiazol-4(5H)-one) that most inhibited tumor cell proliferation. However, the most interesting results were obtained in the study of inhibitory activity towards two 11β-HSD isoforms. Many compounds at a concentration of 10 µM showed significant inhibitory activity against 11β-HSD1 (11β-hydroxysteroid dehydrogenase type 1). The compound 3h (2-(cyclopentylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one) showed the strongest 11β-HSD1 inhibitory effect (IC₅₀ = 0.07 µM) and was more selective than carbenoxolone. Therefore, it was selected as a candidate for further research. Full article

(This article belongs to the Special Issue Targeting Therapy for Cancer)

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17 pages, 6693 KiB

Open AccessArticle

A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment

by Sara Boumya, Silvia Fallarini, Sonia Siragusa, Giovanni Petrarolo, Silvio Aprile, Valentina Audrito, Concettina La Motta, Silvia Garavaglia, Laura Moro and Giulia Pinton

Int. J. Mol. Sci. 2023, 24(7), 6689; https://doi.org/10.3390/ijms24076689 - 3 Apr 2023

Cited by 3 | Viewed by 2736

Abstract

Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor [...] Read more.

Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer. Full article

(This article belongs to the Special Issue Targeting Therapy for Cancer)

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11 pages, 1625 KiB

Open AccessArticle

¹⁹⁸Au-Coated Superparamagnetic Iron Oxide Nanoparticles for Dual Magnetic Hyperthermia and Radionuclide Therapy of Hepatocellular Carcinoma

by Nasrin Abbasi Gharibkandi, Michał Żuk, Fazilet Zumrut Biber Muftuler, Kamil Wawrowicz, Kinga Żelechowska-Matysiak and Aleksander Bilewicz

Int. J. Mol. Sci. 2023, 24(6), 5282; https://doi.org/10.3390/ijms24065282 - 9 Mar 2023

Cited by 11 | Viewed by 2324

Abstract

This study was performed to synthesize a radiopharmaceutical designed for multimodal hepatocellular carcinoma (HCC) treatment involving radionuclide therapy and magnetic hyperthermia. To achieve this goal, the superparamagnetic iron oxide (magnetite) nanoparticles (SPIONs) were covered with a layer of radioactive gold (¹⁹⁸Au) [...] Read more.

This study was performed to synthesize a radiopharmaceutical designed for multimodal hepatocellular carcinoma (HCC) treatment involving radionuclide therapy and magnetic hyperthermia. To achieve this goal, the superparamagnetic iron oxide (magnetite) nanoparticles (SPIONs) were covered with a layer of radioactive gold (¹⁹⁸Au) creating core–shell nanoparticles (SPION@Au). The synthesized SPION@Au nanoparticles exhibited superparamagnetic properties with a saturation magnetization of 50 emu/g, which is lower than reported for uncoated SPIONs (83 emu/g). Nevertheless, the SPION@Au core–shell nanoparticles showed a sufficiently high saturation magnetization value which allows them to reach a temperature of 43 °C at a magnetic field frequency of 386 kHz. The cytotoxic effect of nonradioactive and radioactive SPION@Au–polyethylene glycol (PEG) bioconjugates was carried out by treating HepG2 cells with various concentrations (1.25–100.00 µg/mL) of the compound and radioactivity in range of 1.25–20 MBq/mL. The moderate cytotoxic effect of nonradioactive SPION@Au-PEG bioconjugates on HepG2 was observed. The cytotoxic effect associated with the β⁻ radiation emitted by ¹⁹⁸Au was much greater and already reaches a cell survival fraction below 8% for 2.5 MBq/mL of radioactivity after 72 h. Thus, the killing of HepG2 cells in HCC therapy should be possible due to the combination of the heat-generating properties of the SPION-¹⁹⁸Au–PEG conjugates and the radiotoxicity of the radiation emitted by ¹⁹⁸Au. Full article

(This article belongs to the Special Issue Targeting Therapy for Cancer)

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20 pages, 2756 KiB

Open AccessArticle

Biological Activity of Oleanolic Acid Derivatives HIMOXOL and Br-HIMOLID in Breast Cancer Cells Is Mediated by ER and EGFR

by Natalia Lisiak, Patrycja Dzikowska, Urszula Wisniewska, Mariusz Kaczmarek, Barbara Bednarczyk-Cwynar, Lucjusz Zaprutko and Blazej Rubis

Int. J. Mol. Sci. 2023, 24(6), 5099; https://doi.org/10.3390/ijms24065099 - 7 Mar 2023

Cited by 5 | Viewed by 1988

Abstract

Breast cancer is one of the most frequently observed malignancies worldwide and represents a heterogeneous group of cancers. For this reason, it is crucial to properly diagnose every single case so a specific and efficient therapy can be adjusted. One of the most [...] Read more.

Breast cancer is one of the most frequently observed malignancies worldwide and represents a heterogeneous group of cancers. For this reason, it is crucial to properly diagnose every single case so a specific and efficient therapy can be adjusted. One of the most critical diagnostic parameters evaluated in cancer tissue is the status of the estrogen receptor (ER) and epidermal growth factor receptor (EGFR). Interestingly, the expression of the indicated receptors may be used in a personalized therapy approach. Importantly, the promising role of phytochemicals in the modulation of pathways controlled by ER and EGFR was also demonstrated in several types of cancer. One such biologically active compound is oleanolic acid, but due to poor water solubility and cell membrane permeability that limits its use, alternative derivative compounds were developed. These are HIMOXOL and Br-HIMOLID, which were demonstrated to be capable of inducing apoptosis and autophagy or diminishing the migratory and invasive potential of breast cancer cells in vitro. In our study, we revealed that proliferation, cell cycle, apoptosis, autophagy, and also the migratory potential of HIMOXOL and Br-HIMOLID in breast cancer cells are mediated by ER (MCF7) and EGFR (MDA-MB-231) receptors. These observations make the studied compounds interesting in the context of anticancer strategies. Full article

(This article belongs to the Special Issue Targeting Therapy for Cancer)

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10 pages, 13340 KiB

Open AccessArticle

A Thiosemicarbazone Derivative as a Booster in Photodynamic Therapy—A Way to Improve the Therapeutic Effect

by Robert Gawecki, Jaroslaw Polanski and Anna Mrozek-Wilczkiewicz

Int. J. Mol. Sci. 2022, 23(23), 15370; https://doi.org/10.3390/ijms232315370 - 6 Dec 2022

Cited by 1 | Viewed by 1915

Abstract

Photodynamic therapy is one of the most patient friendly and promising anticancer therapies. The active ingredient is irradiated protoporphyrin IX, which is produced in the body that transfers energy to the oxygen-triggering phototoxic reaction. This effect could be enhanced by using iron chelators, [...] Read more.

Photodynamic therapy is one of the most patient friendly and promising anticancer therapies. The active ingredient is irradiated protoporphyrin IX, which is produced in the body that transfers energy to the oxygen-triggering phototoxic reaction. This effect could be enhanced by using iron chelators, which inhibit the final step of heme biosynthesis, thereby increasing the protoporphyrin IX concentration. In the presented work, we studied thiosemicarbazone derivative, which is a universal enhancer of the phototoxic effect. We examined several genes that are involved in the transport of the heme substrates and heme itself. The results indicate that despite an elevated level of ABCG2, which is responsible for the PpIX efflux, its concentration in a cell is sufficient to trigger a photodynamic reaction. This effect was not observed for 5-ALA alone. The analyzed cell lines differed in the scale of the effect and a correlation with the PpIX accumulation was observed. Additionally, an increased activation of the iron transporter MFNR1 was also detected, which indicated that the regulation of iron transport is essential in PDT. Full article

(This article belongs to the Special Issue Targeting Therapy for Cancer)

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Review

Jump to: Research, Other

19 pages, 1738 KiB

Open AccessReview

A Glimpse into Dendrimers Integration in Cancer Imaging and Theranostics

by Adriana Cruz, José Barbosa, Patrícia Antunes, Vasco D. B. Bonifácio and Sandra N. Pinto

Int. J. Mol. Sci. 2023, 24(6), 5430; https://doi.org/10.3390/ijms24065430 - 12 Mar 2023

Cited by 13 | Viewed by 2461

Abstract

Cancer is a result of abnormal cell proliferation. This pathology is a serious health problem since it is a leading cause of death worldwide. Current anti-cancer therapies rely on surgery, radiation, and chemotherapy. However, these treatments still present major associated problems, namely the [...] Read more.

Cancer is a result of abnormal cell proliferation. This pathology is a serious health problem since it is a leading cause of death worldwide. Current anti-cancer therapies rely on surgery, radiation, and chemotherapy. However, these treatments still present major associated problems, namely the absence of specificity. Thus, it is urgent to develop novel therapeutic strategies. Nanoparticles, particularly dendrimers, have been paving their way to the front line of cancer treatment, mostly for drug and gene delivery, diagnosis, and disease monitoring. This is mainly derived from their high versatility, which results from their ability to undergo distinct surface functionalization, leading to improved performance. In recent years, the anticancer and antimetastatic capacities of dendrimers have been discovered, opening new frontiers to dendrimer-based chemotherapeutics. In the present review, we summarize the intrinsic anticancer activity of different dendrimers as well as their use as nanocarriers in cancer diagnostics and treatment. Full article

(This article belongs to the Special Issue Targeting Therapy for Cancer)

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18 pages, 687 KiB

Open AccessReview

Cell Immunotherapy against Melanoma: Clinical Trials Review

by Ivan Y. Filin, Yuri P. Mayasin, Chulpan B. Kharisova, Anna V. Gorodilova, Kristina V. Kitaeva, Daria S. Chulpanova, Valeriya V. Solovyeva and Albert A. Rizvanov

Int. J. Mol. Sci. 2023, 24(3), 2413; https://doi.org/10.3390/ijms24032413 - 26 Jan 2023

Cited by 9 | Viewed by 3509

Abstract

Melanoma is one of the most aggressive and therapy-resistant types of cancer, the incidence rate of which grows every year. However, conventional methods of chemo- and radiotherapy do not allow for completely removing neoplasm, resulting in local, regional, and distant relapses. In this [...] Read more.

Melanoma is one of the most aggressive and therapy-resistant types of cancer, the incidence rate of which grows every year. However, conventional methods of chemo- and radiotherapy do not allow for completely removing neoplasm, resulting in local, regional, and distant relapses. In this case, adjuvant therapy can be used to reduce the risk of recurrence. One of the types of maintenance cancer therapy is cell-based immunotherapy, in which immune cells, such as T-cells, NKT-cells, B cells, NK cells, macrophages, and dendritic cells are used to recognize and mobilize the immune system to kill cancer cells. These cells can be isolated from the patient’s peripheral blood or biopsy material and genetically modified, cultured ex vivo, following infusion back into the patient for powerful induction of an anti-tumor immune response. In this review, the advantages and problems of the most relevant methods of cell-based therapy and ongoing clinical trials of adjuvant therapy of melanoma are discussed. Full article

(This article belongs to the Special Issue Targeting Therapy for Cancer)

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Other

Jump to: Research, Review

7 pages, 761 KiB

Open AccessCase Report

Combining Three Tyrosine Kinase Inhibitors: Drug Monitoring Is the Key

by Quentin Dominique Thomas, Nelly Firmin, Litaty Mbatchi, Alexandre Evrard, Xavier Quantin and Fanny Leenhardt

Int. J. Mol. Sci. 2023, 24(6), 5518; https://doi.org/10.3390/ijms24065518 - 14 Mar 2023

Cited by 4 | Viewed by 2237

Abstract

A combination of tyrosine kinase inhibitors (TKIs) is likely to be a therapeutic option for numerous oncological situations due to high frequency of oncogenic addiction and progress in precision oncology. Non-small cell lung cancer (NSCLC) represents a subtype of tumors for which oncogenic [...] Read more.

A combination of tyrosine kinase inhibitors (TKIs) is likely to be a therapeutic option for numerous oncological situations due to high frequency of oncogenic addiction and progress in precision oncology. Non-small cell lung cancer (NSCLC) represents a subtype of tumors for which oncogenic drivers are frequently involved. To the best of our knowledge, we report the first case of a patient treated with three different TKIs. Osimertinib and crizotinib were administered concurrently for an epidermal growth factor receptor (EGFR)-mutated NSCLC developing a MET amplification as a resistance mechanism to osimertinib. Simultaneously, imatinib was administered for a metastatic gastrointestinal stromal tumor. The progression-free survival was 7 months for both tumors with this tritherapy. The use of therapeutic drug monitoring to assess plasma concentrations of each TKI was a powerful tool to manage the toxicity profile of this combination (creatine phosphokinase elevation) while preserving an optimal exposure to each TKI and treatment efficacy. We observed an imatinib over-exposition related to crizotinib introduction, probably explained by drug–drug interaction mediated by crizotinib enzymatic inhibition on cytochrome P-450 3A4. Posology adjustment due to therapeutic drug monitoring was probably involved in the good survival outcome of the patient. This tool should be used more routinely for patients treated by TKIs to prevent co-treatment interactions and, in particular, for patients receiving TKI combinations to obtain optimal therapeutic exposure and efficacy while reducing possible side-effects. Full article

(This article belongs to the Special Issue Targeting Therapy for Cancer)

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