Synergistic Effect of Simultaneous versus Sequential Combined Treatment of Histone Deacetylase Inhibitor Valproic Acid with Etoposide on Melanoma Cells.

Yueh-Ming Shyu,Lawrence Yu-Min Liu,Yung-Jen Chuang

doi:10.3390/ijms221810029

Abstract

Melanoma is the most lethal form of skin cancer, which is intrinsically resistant to conventional chemotherapy. Combination therapy has been developed to overcome this challenge and show synergistic anticancer effects on melanoma. Notably, the histone deacetylase inhibitor, valproic acid (VPA), has been indicated as a potential sensitizer of chemotherapy drugs on various metastatic cancers, including advanced melanoma. In this study, we explored whether VPA could serve as an effective sensitizer of chemotherapy drug etoposide (ETO) on B16-F10 and SK-MEL-2-Luc melanoma cell lines in response to drug-induced DNA damages. Our results demonstrated that the VPA-ETO simultaneous combined treatment and ETO pretreated sequential combined treatment generated higher inhibitory effectivities than the individual treatment of each drug. We found the VPA-ETO simultaneous combined treatment contributed to the synergistic inhibitory effect by the augmented DNA double-strand breaks, accompanied by a compromised homologous recombination activity. In comparison, the ETO pretreated sequential combined treatment led to synergistic inhibitory effect via enhanced apoptosis. Surprisingly, the enhanced homologous recombination activity and G2/M phase arrest resulted in the antagonistic effect in both cells under VPA pretreated sequential combined treatment. In summary, our findings suggested that sequential order and effective dose of drug administration in VPA-ETO combination therapy could induce different cellular responses in melanoma cells. Such understanding might help potentiate the effectiveness of melanoma treatment and highlight the importance of sequential order and effective dose in combination therapy.

Highlights

IntroductionMelanoma is an aggressive cancer type with high metastatic potential
We first evaluated the efficacies of single treatments of valproic acid (VPA) or ETO on murine melanoma cell line B16-F10 and human melanoma cell line SK-MEL-2-Luc to determine the IC50 values of each drug
The results demonstrated that the single treatments of VPA or ETO had dose-dependent inhibitory effects on B16-F10 and SK-MEL-2-Luc cells (Figure 1)

Summary

Introduction

Melanoma is an aggressive cancer type with high metastatic potential. Ten percent of melanoma patients are already advanced stage at diagnosis [1]. When tumor cells disseminating to the lungs and liver, radiation therapy is ineffective in controlling the cancer progression [2]. Systemic therapies such as chemotherapy, targeted therapy, and immunotherapy are preferred treatment options. There are limitations to these therapies, including the development of resistance or second mutations [3]. Chemotherapy is still the major systemic therapy for many patients due to affordability constraints. There remains a need for chemotherapy-based strategies for advanced melanoma

Methods

Results

Conclusion