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.
Highlights
Lung, breast, and colorectal cancers are the leading causes of cancerrelated deaths despite many therapeutic options, including targeted therapy and immunotherapies
To further study the therapeutic potential of PTC-209, we investigated whether its anti-growth effects could enhance the anticancer activity of major chemotherapeutic drugs, namely, cisplatin on lung cancer cells; LNM35 and A549; camptothecin on breast cancer cells, MDA-MB-231; oxaliplatin and 5-fluorouracil on colon cancer cell, HT-29
We investigated the impact of the combination PTC-209 and a natural triterpenoid glycoside, Frondoside A, on six different cell lines, namely, LNM35, A549, MDA-MB-231, HT-29, HCT-116, and mouse gastric stem cells (MGSC)
Summary
Breast, and colorectal cancers are the leading causes of cancerrelated deaths despite many therapeutic options, including targeted therapy and immunotherapies. Lung, breast, and colorectal cancers are the leading causes of cancer-related deaths, despite many therapeutic options, including targeted therapies and immunotherapies. The anti-cancer potential of PTC-209, a small specific inhibitor of Bmi-1, has been evaluated and showed efficacy, in vitro and in vivo, against various human cancers, such as colorectal (Kreso et al, 2014), ovarian (Dey et al, 2016), glioblastoma (Kong et al, 2018), head neck squamous cell carcinoma (Wang et al, 2017), multiple myeloma (MM) (Alzrigat et al, 2017), and chronic and acute myeloid leukemia (Nishida et al, 2015). Further studies showed that PTC-209 downregulated the level of Bmi-1 protein without affecting the levels of Bmi-1 transcript in MM cells (Wang et al, 2017) and biliary tract cancer (BTC) cells (Mayr et al, 2016), suggesting that it might regulate Bmi-1 expression at the posttranscriptional level
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