PTC-209 Anti-Cancer Effects Involved the Inhibition of STAT3 Phosphorylation

Shahrazad Sulaiman; Kholoud Arafat; Rabah Iratni; Samir Attoub

doi:10.3389/fphar.2019.01199

PTC-209 Anti-Cancer Effects Involved the Inhibition of STAT3 Phosphorylation

Front Pharmacol. 2019 Oct 21:10:1199. doi: 10.3389/fphar.2019.01199. eCollection 2019.

Authors

Shahrazad Sulaiman¹, Kholoud Arafat¹, Rabah Iratni², Samir Attoub^{1

3}

Affiliations

¹ Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
² Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates.
³ Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.

Abstract

Introduction: Lung, breast, and colorectal cancers are the leading causes of cancer-related deaths despite many therapeutic options, including targeted therapy and immunotherapies. Methods: Here, we investigated the impact of PTC-209, a small-molecule Bmi-1 inhibitor, on human cancer cell viability alone and in combination with anticancer drugs, namely, cisplatin, oxaliplatin, 5-fluorouracil, camptothecin, and Frondoside-A and its impact on cellular migration and colony growth in vitro and on tumor growth in ovo. Results: We demonstrate that PTC-209 causes a concentration- and time-dependent decrease in the cellular viability of lung cancer cells (LNM35 and A549), breast cancer cells (MDA-MB-231 and T47D), and colon cancer cells (HT-29, HCT8/S11, and HCT-116). Similarly, treatment with PTC-209 significantly decreased the growth of LNM35, A549, MDA-MB-231, and HT-29 clones and colonies in vitro and LNM35 and A549 tumor growth in the in ovo tumor xenograft model. PTC-209 at the non-toxic concentrations significantly reduced the migration of lung (LNM35 and A549) and breast (MDA-MB-231) cancer cells. Moreover, we show that PTC-209, at a concentration of 1 μM, enhances the anti-cancer effects of Frondoside-A in lung, breast, and colon cancer cells, as well as the effect camptothecin in breast cancer cells and the effect of cisplatin in lung cancer cells in vitro. However, PTC-209 failed to enhance the anti-cancer effects of oxaliplatin and 5-fluorouracil in colon cancer cells. Treatment of lung, breast, and colon cancer cells with PTC-209 (1 and 2.5 μM) for 48 h showed no caspase-3 activation, but a decrease in the cell number below the seeding level suggests that PTC-209 reduces cellular viability probably through inhibition of cell proliferation and induction of cell death via a caspase-3-independent mechanism. Molecular mechanism analysis revealed that PTC-209 significantly inhibited the STAT3 phosphorylation by decreasing the expression level of gp130 as early as 30 min post-treatment. Conclusion: Our findings identify PTC-209 as a promising anticancer agent for the treatment of solid tumors either alone and/or in combination with the standard cytotoxic drugs cisplatin and camptothecin and the natural product Frondoside-A.

Keywords: Bmi-1; Frondoside-A; PTC-219; STAT3; cisplatin.