2. Academic Validation
  3. NEO212 induces mitochondrial apoptosis and impairs autophagy flux in ovarian cancer

NEO212 induces mitochondrial apoptosis and impairs autophagy flux in ovarian cancer

  • J Exp Clin Cancer Res. 2019 Jun 7;38(1):239. doi: 10.1186/s13046-019-1249-1.
Xingguo Song 1,  Lisheng Liu 2 3,  Minghui Chang 4 3,  Xinran Geng 5,  Xingwu Wang 1,  Weijun Wang 6,  Thomas C Chen 6,  Li Xie 1 3,  Xianrang Song 7 8
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China.
  • 2 Key Laboratory of Animal Resistance Research, College of Life Science, Shandong Normal University, 88 East Wenhua Road, Jinan, Shandong, People's Republic of China.
  • 3 Department of Clinical Laboratory, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China.
  • 4 School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.
  • 5 Maternity & Child Care Center of Dezhou, Dongdizhong Street 835#, Decheng District, Dezhou, Shandong, People's Republic of China.
  • 6 Departments of Neurological Surgery, and Pathology, University of Southern California, Los Angeles, California, USA.
  • 7 Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China. [email protected].
  • 8 Department of Clinical Laboratory, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China. [email protected].
PMID: 31174569 DOI: 10.1186/s13046-019-1249-1
Abstract

Background: 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.. In the current study, we intend to illuminate the potential Anticancer property and the underly mechanisms of NEO212 in ovarian Cancer cells.

Methods: The 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.

Results: NEO212 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).

Conclusions: NEO212 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.

Keywords

Autophagic flux; Mitochondrial apoptosis; NEO212; Ovarian cancer; TFEB.

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