Abstract 4833: CDODA-Me augments the efficacy of chemotherapeutic agents and overcomes chemo-resistance in breast and lung cancer cells

Abstract

Abstract Purpose: The purpose of this research is to determine the effects of the combination of (CDODA-Me), a derivative of glycyrrhetinic acid with chemotherapeutic agents like docetaxel (DTX) and Erlotinib (a TKI inhibitor) to treat triple negative breast cancer (TNBC) and TKI resistant lung cancer. Methods: TNBC lines MDA-MB-231 MDA-MB-468 and DTX resistant (MDA231) cells were treated in combination with CDODA-Me (nontoxic dose of 2 μM) and DTX. Wildtype (HCC827) and resistant (Erlotinib resistant) lung cancer cells were treated with Erlotinib and CDODA-Me. The cell viability of MDA-MB-231, MDA-MB-468, Docetaxel resistant (MDA231) cells and HCC 827 Erlotinib resistant (4 μM) cells in each treatment group was determined by crystal violet assay. Combination index values were calculated by isobolographic analysis. Western blot annalysis was used to investigate the influence of CDODA-Me combinations on drug resistance and key apoptotic proteins such as bcl2, survivin, SP1, SP3, and SP4. 2’,7’ -dichlorofluorescin diacetate (DCFDA) was used to measure reactive oxygen species (ROS) levels in all cell lines and examined by flowcytometry. Results: Breast Cancer cells (MDA-MB-468 and MDA-MB-231) showed increased cytotoxicity with a ten fold decrease in IC50 concentration (0.3 μM DTX and 0.03 μM DTX in combination with 2 μM CDODA-Me). DTX resistant (MDA231) cells showed IC50 values comparable to wildtype cells at 0.29 μM DTX in combination with CDODA-Me. HCC827 (Erlotinib resistant) showed a three fold decrease in cytotoxicity (IC 50 values of 4.9 μM and 16.9 μM Erlotinib for the combination and Erlotinib alone respectively). The combination treatment also showed higher response in resistant cells with IC50 values comparable to wildtypes. The expression of bcl2, survivin, specific transcription factors (like SP1, SP3 and SP4) was downregulated in cells treated with CDODA-ME and DTX combination compared to CDODA-ME alone, DTX alone and control cells. Similar results were observed with CDODA-Me and Erlotinib combination in HCC827 erlotonib resistant (4 μM) cells. CDODA-Me alone treatment showed ROS levels in HCC 827 (4 μM) resistant cell lines were increased (8-fold) significantly as compared to other breast cancer cells. Conclusion: In conclusion, CDODA-Me inhibits growth of TNBC cells and Erlotinib resistant lung cancer cells and downregulates the SP proteins and anti-apoptotic proteins. Therefore, these results indicate that CDODA-Me is a promising anticancer agent and can overcome resistance of chemotherapeutic agents against breast and lung cancer. Citation Format: Ebony Nottingham, Ravi Doddapaneni, Mandip Sachdeva. CDODA-Me augments the efficacy of chemotherapeutic agents and overcomes chemo-resistance in breast and lung cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4833.