OT-304, a unique antitumor agent with multiple inhibitory effects on the cell cycle, cancer cell proliferation and the development of drug resistance

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Abnormal proliferative rate, increased angiogenesis, and the development of resistance to chemotherapy are among the major features of cancer. Accordingly, an ideal comprehensive anti-tumor strategy includes agents that target simultaneously these three processes. In the present study, we have characterized the anti-tumor effects of a novel small molecule dual inhibitor of NF-κB, OT-304. This compound was found to exert profound inhibitory effects on the proliferation of the following human cancer cell lines: D-54 and U-97 glioblastoma (mean inhibition + SEM = 89 + 5%; P < 0.001); MCF-7 breast cancer (78 + 6%, p < 0.001); H-1299 lung cancer (69 + 7%, P < 0.001); PC-3 prostate cancer (71 + 6%, P < 0.001); HL-60 acute leukemia, (55 + 5%, P < 0.01) and U-937 lymphoma (50 + 4%, P < 0.01) at 10 uM and over 24-72 hours. Analysis of the underlying mechanism(s) indicated that at low concentrations, 1-10 uM, OT304 induces a G0/G1 cell cycle arrest. High concentrations of OT-304 (100 uM) induces cancer cell apoptosis. OT-304 also effectively inhibits the proliferation of doxorubicin (dox)-sensitive and dox-resistant cells to the same extent for both cell lines suggesting that it may suppress the development of drug resistance. OT-304 enhanced by at least 10 times cancer cell sensitivity to dox and to etoposide in cells selected for resistance to these drugs and characterized by over-expression of the drug transporter P-glycoprotein. The latter findings suggests that either the expression/and or the function of P-glycoprotein could be affected by OT-304. In vivo studies of human tumor xenografts in nude mice showed that OT-304 (30 mg/Kg, IP every three days) was able to inhibit the growth of dox-resistant MCF-7 by more than 80% (tumor volume (mm³) 2,643 + 832 in control group versus OT304-treated 416 + 209, P < 0.001) at the end of the study on day 24. When combined with dox (2 mg/Kg), the inhibitory effect was more than 95% (724 + 450 mm³ in dox treated group versus 164 + 79 mm³ in OT-304 plus dox treated group) on day 24. Together, these findings provide evidence that OT-304 acts through multiple mechanisms to prevent cancer progression and suppress the development of drug resistance. Further pre-clinical and clinical studies are warranted to determine the efficacy of OT-304 in treating a broad spectrum of human tumors.