NEO212 induces mitochondrial apoptosis and impairs autophagy flux in ovarian cancer

Xingguo Song,Xingwu Wang,Weijun Wang,Xinran Geng,Xianrang Song,Thomas C Chen,Li Xie,Minghui Chang,Lisheng Liu

doi:10.1186/s13046-019-1249-1

Abstract

BackgroundTemozolomide-perillyl alcohol conjugate (NEO212), a novel temozolomide (TMZ) analog, was previously reported to exert its anti-cancer effect in non-small cell lung cancer (NSCLC), and human nasopharyngeal carcinoma (NPC), etc.. In the current study, we intend to illuminate the potential anticancer property and the underly mechanisms of NEO212 in ovarian cancer cells.MethodsThe cytotoxicity of NEO212 was detected by MTT, colony formation analysis and xenograft model. The proteins involved in cell proliferation, DNA damage, autophagy and lysosomal function were detected by western blots; mitochondria, lysosome and autophagosome were visualized by TEM and/or immunofluorescence; Apoptosis, cell cycle analysis and mitochondrial transmembrane potential were detected by flow cytometry. TFEB translocation was detected by immunofluorescence and western blot.ResultsNEO212 has the potential anticancer property in ovarian cancer cells, as evidence from cell proliferation inhibition, G2/M arrest, DNA damage, xenograft, mitochondrial dysfunction and apoptosis. Importantly, we observed that although it induced significant accumulation of autophagosomes, NEO212 quenched GFP-LC3 degradation, down-regulated a series of lysosome related gene expression and blocked the autophagic flux, which significantly facilitated it induced apoptosis and was largely because it inhibited the nuclear translocation of transcription factor EB (EB).ConclusionsNEO212 inhibited TFEB translocation, and impaired the lysosomal function, implying NEO212 might avoid from autophagy mediated chemo-resistance, thus proposing NEO212 as a potential therapeutic candidate for ovarian cancer.

Highlights

Temozolomide-perillyl alcohol conjugate (NEO212), a novel temozolomide (TMZ) analog, was previously reported to exert its anti-cancer effect in non-small cell lung cancer (NSCLC), and human nasopharyngeal carcinoma (NPC), etc
We found that NEO212 exerted an antitumor effect in ovarian cancer, as evidence from cell proliferation inhibition, G2/M arrest, DNA damage, xenograft, mitochondrial fission and apoptosis
We observed that NEO212 blocked autophagy flux the number of autophagosomes was increased, which significantly facilitated it induced apoptosis and was largely because NEO212 inhibited the nuclear translocation of transcription factor EB (EB), and impaired the lysosomal function, proposing NEO212 as a potential therapeutic candidate for ovarian cancer

Summary

Introduction

Temozolomide-perillyl alcohol conjugate (NEO212), a novel temozolomide (TMZ) analog, was previously reported to exert its anti-cancer effect in non-small cell lung cancer (NSCLC), and human nasopharyngeal carcinoma (NPC), etc. Temozolomide-perillyl alcohol conjugate (NEO212), a novel temozolomide (TMZ) analog, is developed based on the conjugation of TMZ, a clinically applied alkylating agent, and perillyl alcohol (POH), a naturally occurring monoterpene that has been used orally for the treatment of a variety of cancers [4]. This novel compound has recently attracted continuous attention since accumulating data demonstrate that it exhibits stronger. Fission is needed to create new mitochondria, but it can facilitate apoptosis during high levels of cellular stress [12] such as chemical reagent treatment. Our previous studies have demonstrated that NEO212 was capable of inducing ROS accumulation, mitochondrial membrane potential collapse and mitochondrial apoptosis [7, 9], indicating mitochondria might be one of main targets of NEO212

Objectives

Methods

Results

Discussion

Conclusion