Fraxetin Interacts Additively with Cisplatin and Mitoxantrone, Antagonistically with Docetaxel in Various Human Melanoma Cell Lines—An Isobolographic Analysis

Abstract

Malignant melanoma is a skin cancer characterized by rapid development, poor prognosis and high mortality. Due to the frequent drug resistance and/or early metastases in melanoma, new therapeutic methods are urgently needed. The study aimed at assessing the cytotoxic and antiproliferative effects of scoparone and fraxetin in vitro, when used alone and in combination with three cytostatics: cisplatin, mitoxantrone, and docetaxel in four human melanoma cell lines. Our experiments showed that scoparone in the concentration range tested up to 200 µM had no significant effect on the viability of human malignant melanoma (therefore, it was not possible to evaluate it in combination with other cytostatics), while fraxetin inhibited cell proliferation with IC50 doses in the range of 32.42–73.16 µM, depending on the cell line. Isobolographic analysis allowed for the assessment of the interactions between the studied compounds. Importantly, fraxetin was not cytotoxic to normal keratinocytes (HaCaT) and melanocytes (HEMa-LP), although it slightly inhibited their viability at high concentrations. The combination of fraxetin with cisplatin and mitoxantrone showed the additive interaction, which seems to be a promising direction in melanoma therapy. Unfortunately, the combination of fraxetin with docetaxel may not be beneficial due to the antagonistic antiproliferative effect of both drugs used in the mixture.

Synergy, Additivity and Antagonism between Esculetin and Six Commonly Used Chemotherapeutics in Various Malignant Melanoma Cell Lines—An Isobolographic Analysis

“…Thus, our experiments and isobolographic analysis showed that the combinations of esculetin and cisplatin are characterized by additive interactions. An additive interaction was also observed for the combination of cisplatin and osthole for two melanoma cell lines, FM55P and FM55M2 [5], and for the combination of cisplatin with fraxetin (7,8-dihydroxy-6-methoxycoumarin) for four malignant melanoma cell lines [6]. Our experiments showed that the combinations of esculetin with taxanes (paclitaxel and docetaxel) also showed additive interactions, although the combination of fraxetin with docetaxel showed an additive interaction with a tendency to antagonism [6], which may be due to the different chemical structure of fraxetin compared to esculetin.…”

“…They can be used not only in the prevention of cancer but also in its treatment. Tested individually (for a better understanding of the mechanisms of anticancer activity) or in combination with other substances, they become an interesting target for the development of more beneficial forms of therapy [4][5][6].…”

Esculetin unveiled: Decoding its anti‐tumor potential through molecular mechanisms—A comprehensive review

“…Combination of these drugs with esculetin decreases cell viability, cell proliferation, and cytotoxicity, including arrest of the cell cycle in the G1 phase, induction of cytochrome c, p53, p21, and p27 expression, reduction of CDK2 and CDK4 expression and prevention the binding interaction between Nrf2 and KEAP-1 in the range of concentrations of 2-200 μM in human malignant melanoma cell lines (FM55P, A375, FM55M2, and SK-MEL28). 96 Morin, and esculetin supplementation effectively target tumor metabolism via β-cateinin/cmyc signaling and affect glycolysis and glutaminolysis to abrogate colon cancer in rats. 47 Regarding treating leukemia, the combined use A summary of the combined effect of esculetin with other phytochemical and chemotherapeutics agents is shortlisted in Table 4.…”

“…Epirubicin, and vemurafenib showed antagonistic interactions with esculetin, while cisplatin, docetaxel, and paclitaxel showed additive interactions with esculetin. Combination of these drugs with esculetin decreases cell viability, cell proliferation, and cytotoxicity, including arrest of the cell cycle in the G1 phase, induction of cytochrome c, p53, p21, and p27 expression, reduction of CDK2 and CDK4 expression and prevention the binding interaction between Nrf2 and KEAP‐1 in the range of concentrations of 2–200 μM in human malignant melanoma cell lines (FM55P, A375, FM55M2, and SK‐MEL28) 96 . Morin, and esculetin supplementation effectively target tumor metabolism via β‐cateinin/c‐myc signaling and affect glycolysis and glutaminolysis to abrogate colon cancer in rats 47 .…”

Novel NF-κB Inhibitor-Conjugated Pt(IV) Prodrug to Enable Cancer Therapy through ROS/ER Stress and Mitochondrial Dysfunction and Overcome Multidrug Resistance

“…Drug combination therapy, using platinum-based antitumor drugs in combination with different target cytotoxic drugs, is an effective strategy to enhance the anticancer efficacy and overcome the drug resistance of platinum drugs in tandem with reduced toxicity. , For example, the combination chemotherapeutic regimen of cisplatin with tubulin inhibitors (e.g., paclitaxel and docetaxel) was used for the treatment of several major solid tumors as a frontline agent in the clinic; − oxaliplatin in combination with folinic acid and 5-fluorouracil as a three-component chemotherapy protocol was used to treat colorectal cancer . However, this strategy of the concurrent use of two or more drugs remains a challenge because of unpredictable drug–drug interactions as each individual drug has its own pharmacokinetic profile as well as toxicity pattern.…”