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Abstract
S5 is a withanolide natural product isolated from Physalis pubescens L. Our previous experimental studies found that it has significant antitumor activity on renal cell carcinoma. In the present study, the anti-melanoma effect of S5 and the related molecular mechanism was first investigated. It was found that S5 induced an obvious growth inhibitory effect on human melanoma A375 cells with low toxicity to human peripheral blood cells. Furthermore, the results demonstrated that the cell death mode of S5 on A375 cells is not due to inducing apoptosis and autophagy. However, there was a significant time-dependent increase in G2/M phase after treatment of A375 with S5. Meanwhile, S5 could also decrease the protein expression of Cdc25c, Cdc2, and CyclinB1, and increased the expression of p-P53 and P21, suggesting that S5 inhibited A375 cell death through G2/M phase arrest. Moreover, the signal pathway factors P38, extracellular regulated protein kinases (ERK), and epidermal growth factor receptor (EGFR) were observed taking part in the S5-induced A375 cells growth inhibitory effect. In addition, suppressing P38 and EGFR reversed the cell proliferation inhibitory effect and G2/M cell cycle arrest induced by S5 and inhibition of EGFR enhanced the downregulation of the expression of P38 and p-P38, indicating that S5 induced A375 G2/M arrest through the EGFR/P38 pathway. Briefly, this study explained for the first time the mechanism of S5-induced A375 cell growth inhibition in order to provide the basis for its clinical application in melanoma.
Highlights
Cutaneous melanoma, the malignant tumor of melanocytes, is the skin cancer with the highest mortality and increasing incidence worldwide [1]
In order to confirm whether S5 inhibits A375 cell proliferation via Mitogen-activated protein kinases (MAPKs) signaling pathway, we examined the effect of the Jun N-terminal kinases (JNKs) inhibitor SP600125, the extracellular regulated protein kinases (ERK) inhibitor PD98059, and the P38 inhibitor SB201580 on the S5-induced growth inhibition of A375 cells
We previously found that a variety of withanolides of Physalis pubescens L. have the effect of inhibiting renal carcinoma, prostate cancer, and melanoma cell proliferation [44]
Summary
The malignant tumor of melanocytes, is the skin cancer with the highest mortality and increasing incidence worldwide [1]. Incidence of malignant cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease [2,3]. The most common chemotherapy drug presently used for melanoma is dacarbazine (DTIC) at present, which is a U.S Food and Drug Administration (FDA)-approved, first-line treatment for patients with. Molecules 2018, 23, 3175 wild-type melanomas [4]. In recent years, some clinical studies show that there is an objective response rate ranging from 7%–13% when DTIC was used [5,6]. Several other chemotherapeutic agents, such as fotemustine, vindesine, and temozolomide, have similar activities comparable to DTIC [7]. A high-efficiency drug is urgently needed for melanoma
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