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Synergistic inhibitory effects of the oxyresveratrol and dacarbazine combination against melanoma cells.

ABSTRACT: Various therapies have been developed to target malignant melanoma, which is associated with a high mortality rate worldwide. Although dacarbazine (DTIC) is employed for treating melanoma, it is associated with several side effects. Hence, patients with melanoma are co-treated with additional drugs to mitigate the side effects of DTIC. In the present study, synergistic therapeutic effects of the DTIC/oxyresveratrol (ORT) combination were examined using the human malignant melanoma WM-266-4 cell line. Treatment with ORT and DTIC inhibited the proliferation of WM-266-4 cells. Compared with those in the ORT- and DTIC-treated groups, the proportion of cells arrested at the S phase, as well as apoptotic rates, were increased in the ORT and DTIC co-treatment group. In WM-266-4 cells, synergistic proliferation-inhibitory activities of the ORT/DTIC combination were assessed based on cell viability and migration, antioxidant capacity, cytokine production, cell cycle arrest, apoptotic rate and protein expression through WST-1 assay, wound healing assay, flow cytometry and western blotting. Furthermore, the expression levels of proteins, including NOTCH, involved in the pathogenesis of solid cancers, such as melanoma, were examined. Overall, the ORT/DTIC combination synergistically promoted cell cycle arrest at the S phase and the apoptosis of WM-266-4 cells. Thus, this combination treatment may serve as a novel therapeutic strategy for treating malignant melanoma.

SUBMITTER: Lee SG

PROVIDER: S-EPMC8299023 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Cantharidin, an active constituent of mylabris, is believed to have anti-tumor activity. Cantharidin selectively inhibit protein phosphatase 2A (PP2A), a repressor of oncogenic kinase pathways (ERK, JNK, NF-κB, and PKC). Cantharidin represses the growth and metastasis of pancreatic cancer cells in vitro. In the present study, we investigated the effects of cantharidin on pancreatic cancer xenografts in vivo. Methods: Cells stably expressing luciferase were used to establish xenograft models. Xenograft growth was evaluated by living imaging. Gene expression was determined using a microarray, real-time PCR, a RayBiotech antibody array, and the Milliplex assay. Results: Surprisingly, cantharidin significantly accelerated xenograft growth. Living imaging showed a rapid distribution of D-luciferin in cantharidin-treated xenografts, suggesting a rich blood supply. Immunohistochemistry confirmed increased angiogenesis. Microarray and antibody array identified upregulated pro-angiogenic and downregulated anti-angiogenic factors. The Milliplex assay suggested elevated secretion of IL-6, IL-8, TNF-α, and VEGF. ERK, JNK, NF-κB, and PKC pathway inhibitors attenuated the cantharidin-induced changes to pro-angiogenic gene expression. PKC pathway-inhibiting tamoxifen or antiangiogenic therapeutics, including Ginsenoside Rg3, bevacizumab, Apatinib, and Endostar antagonized the pro-angiogenic effect of cantharidin or its derivatives. These regimens presented remarkable synergistic antitumor effects in vivo. Conclusion: Although cantharidin presents anti-tumor effects in vitro and has been applied in clinical practice, we revealed an unfavorable pro-angiogenic side effect. We recommend that the clinical application of cantharidin should be performed on the premise of anti-vascularization therapy.

2018-12-06 | GSE114040 | GEO

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