Securinine induces p73-dependent apoptosis preferentially in p53-deficient colon cancer cells

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Sonia RanaDavid N Wald

Abstract

The identification of agents that preferentially kill cancer cells while protecting normal cells offers the potential to overcome toxicities found in many existing chemotherapeutic agents. Because p53 is frequently inactivated in cancer, agents that preferentially kill p53-null cells and protect wild-type p53-expressing cells are highly desirable chemotherapeutic agents. By using pairs of isogenic colon cancer cell lines that differ only in p53 expression (RKO and HCT116), securinine was found to exhibit these properties. Securinine (30 microM) induces apoptosis in 73% of p53-null HCT116 cells (LD(50) 17.5 microM) as opposed to 17.6% of HCT116 parental cells (LD(50) 50 microM) at 72 h after treatment. The mechanism of securinine-mediated death in p53-deficient cells involves the induction of the p53 family member, p73. Interestingly, the proapoptotic protein p73 is down-regulated in colon cancer cells expressing p53. This differential regulation of p73 in a p53-dependent fashion reveals a novel pathway for preferentially targeting cancer cells. In contrast to p53-deficient cells, cells expressing p53 are protected from cell death through the p53-mediated up-regulation of p21. These studies reveal a novel approach to specificall...Continue Reading

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Citations

Apr 21, 2016·ACS Medicinal Chemistry Letters·Marc PerezVirginie Ratovelomanana-Vidal
Jan 23, 2016·European Journal of Medicinal Chemistry·Marc PerezVirginie Ratovelomanana-Vidal
Jun 27, 2015·Experimental Parasitology·Maha M EissaLayla K Younis
Apr 19, 2015·Biotechnology Advances·Franck MorceauMarc Diederich
Nov 1, 2012·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Jianming JuYijun Chen
Jun 28, 2016·European Journal of Medicinal Chemistry·Wen HouWei-Min Chen
Feb 6, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yu-Chia ChenChung-Yee Yuo
Jan 13, 2015·World Journal of Gastroenterology : WJG·Xiao-Lan LiWee-Joo Chng
Nov 1, 2020·Medicinal Research Reviews·Junmin ZhangKuo-Hsiung Lee
Feb 18, 2016·Molecular Cancer Therapeutics·Goutam KaranDavid N Wald
Jul 10, 2021·Oncogene·Sheelarani KarunanithiDavid N Wald

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