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Front. Pharmacol. | doi: 10.3389/fphar.2019.01199

PTC-209 anti-cancer effects involved the inhibition of STAT3 phosphorylation

  • 1United Arab Emirates University, United Arab Emirates

Lung, breast, and colorectal cancers are leading cancer-related deaths despite many therapeutic options including targeted- and immuno-therapies. 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.
We demonstrate that PTC-209, cause a concentration- and time-dependent decrease in the cellular viability of the 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 the 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 suggesting 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 signaling pathway as early as 30 min post-treatment. 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: PTC-209, Frondoside-A, Cisplatin, Bmi-1, stat3

Received: 05 May 2019; Accepted: 17 Sep 2019.

Copyright: © 2019 Sulaiman, Arafat, Iratni and ATTOUB. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Samir ATTOUB, United Arab Emirates University, Al-Ain, Abu Dhabi, United Arab Emirates,