Innovation Pharmaceuticals Inc (IPIX)

[georgejjl]

Kevetrin in combination with metformin???

Mol Cancer Ther. 2017 May 22. pii: molcanther.0763.2016. doi: 10.1158/1535-7163.MCT-16-0763. [Epub ahead of print]
Metformin synergizes with BCL-XL/BCL-2 inhibitor ABT-263 to induce apoptosis specifically in p53-defective cancer cells.

Li X1, Li B1, Ni Z1, Zhou P1, Wang B1, He J2, Xiong H1, Yang F1, Wu Y1, Lyu X1, Zhang Y1, Zeng Y1, Lian J1, He F3.
Author information
Abstract
p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the pro-apoptotic machineries in various p53-defective cancer cells. Mechanistic studies revealed that metformin sensitized ABT-263 via attenuating mTORC1-mediated cap-dependent translation of MCL-1 and SURVIVIN, and weakening internal ribosome entry site (IRES)-dependent translation of XIAP Meanwhile, ABT-263 sensitized metformin through disrupting the BCL-XL/BIM complex. However, metformin and ABT-263 had no synergistic killing effect in p53 wild type (p53-WT) cancer cells because the cotreatment dramatically induced the senescence-associated secretory phenotype (SASP) in the presence of wild type p53, and SASP could aberrantly activate the AKT/ERK-mTORC1-4EBP1-MCL-1/SURVIVIN signaling axis. Blocking the axis using corresponding kinase inhibitors or neutralizing antibodies against different SASP components sensitized the cotreatment effect of metformin and ABT-263 in p53-WT cancer cells. The in vivo experiments showed that metformin and ABT-263 synergistically inhibited the growth of p53-defective (but not p53-WT) cancer cells in tumor-xenograft nude mice.These results suggest that the combination of metformin and ABT-263 may be a novel targeted therapeutic strategy for p53-defective cancers.

https://www.ncbi.nlm.nih.gov/pubmed/28533436

Good luck and GOD bless,

George