A Novel Anticancer Stem Cell Compound Derived from Pleuromutilin Induced Necroptosis of Melanoma Cells

Abstract

Necroptosis has been recently confirmed as a nonapoptotic form of programmed cell death. Discovery of novel chemical entities, capable of inducing necroptosis of cancer cells, is likely to act as an alternative strategy for dealing with drug resistance clinically. In this study, the identification of a novel Pleuromutilin derivative (compound 38) is presented, capable of significantly increasing the cellular level of ROS and inducing melanoma cancer cell death via necroptosis. Furthermore, compound 38 noticeably ablated various cancer stem cells and inhibited the growth of melanoma cancer cells both in vitro and in vivo. Moreover, 38 exhibited low toxicity in animal models and excellent PK properties, which is currently being verified as a potential anticancer drug candidate.

Development and Validation of a Novel Survival Model for Cutaneous Melanoma Based on Necroptosis-Related Genes

“…Furthermore, decreased RIPK3 predicted a worse prognosis in SKCM ( 10 ). Thus, therapeutic methods targeting necroptosis have attracted significant attention ( 11 , 12 ).…”

Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

“…Similarly, (±)gossypol, natural isomers extracted from cottonseed, has been reported to upregulate the phosphorylation of RIPK3, inducing necroptosis and exerting compelling antiproliferative activity with an IC 50 of 1.7 μmol/L in SCL-1 cutaneous squamous cell carcinoma cells 276 . Moreover, compound 38 , a pleuromutilin derivative has been identified as a novel necroptosis inducer that produced ROS and upregulated the phosphorylation of RIPK3, reducing the viability of A375 and B16F10 cells with IC 50 values of 1.669 and 0.746 μmol/L, respectively, and effectively inhibited melanoma cells invasion; and, compound 38 also has been identified as an orally bioavailable anticancer compound that slowed tumor growth in the A375 xenograft and B16F10 syngeneic models with low toxicity 277 . Apurinic/apyrimidinic endonuclease 1 (APE1), a critical enzyme in DNA repair, is often expressed in abnormally elevated levels in multiple cancers and has been regarded as a promising cancer biomarker 278 , 279 .…”

Harnessing the Potential of Non-Apoptotic Cell Death Processes in the Treatment of Drug-Resistant Melanoma

“…In addition, scientists also identified a novel Pleuromutilin derivative called compound 38 as an anticancer drug candidate [ 97 ]. This compound has demonstrated the ability to significantly increase ROS levels in melanoma cancer stem cells and consequentially induce cell death via necroptosis.…”