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Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer.

Molecular cancer therapeutics (2017-11-22)
Anindya Dey, Xunhao Xiong, Aleia Crim, Shailendra Kumar Dhar Dwivedi, Soumyajit Banerjee Mustafi, Priyabrata Mukherjee, Liangxian Cao, Nadiya Sydorenko, Ramil Baiazitov, Young-Choon Moon, Melissa Dumble, Thomas Davis, Resham Bhattacharya
ABSTRACT

BMI-1, also known as a stem cell factor, is frequently upregulated in several malignancies. Elevated expression of BMI-1 correlates with poor prognosis and is therefore considered a viable therapeutic target in a number of malignancies including ovarian cancer. Realizing the immense pathologic significance of BMI-1, small-molecule inhibitors against BMI-1 are recently being developed. In this study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by posttranslational modification. We report that PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays, whereas normal cells remain unaffected. Mechanistically, hyperphosphorylation-mediated depletion of cellular BMI-1 by PTC-028 coupled with a concurrent temporal decrease in ATP and a compromised mitochondrial redox balance potentiates caspase-dependent apoptosis. In vivo, orally administered PTC-028, as a single agent, exhibits significant antitumor activity comparable with the standard cisplatin/paclitaxel therapy in an orthotopic mouse model of ovarian cancer. Thus, PTC-028 has the potential to be used as an effective therapeutic agent in patients with epithelial ovarian cancer, where treatment options are limited. Mol Cancer Ther; 17(1); 39-49. ©2017 AACR.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Rabbit IgG (whole molecule)–Peroxidase antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
PTC-209, ≥98% (HPLC)
Sigma-Aldrich
Anti-Mouse IgG (whole molecule)–Peroxidase antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
MISSION® esiRNA, targeting human BMI1, COMMD3-BMI1