Abstract
Abstract Background: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to overactive intrinsic mechanisms that mediate cellular proliferation and drug resistance. Dysregulated cell division due to increased activity of cyclin-dependent kinases 4/6 (CDK4/6) is one such mechanism that drives progression of UGCs, making them an important therapeutic target. Palbociclib is a second generation cdk4/6 specific inhibitor approved for treatment of ER+ breast cancers. Since Cisplatin (CDDP) is a first line therapeutic agent frequently used for treatment of UGCs we hypothesized that Palbociclib would complement the DNA-damaging activity of CDDP. To test this hypothesis, we investigated the potential therapeutic benefit of Palbociclib alone and in combination with CDDP in P53 mutant model of UGCs. Methods: In this study, we evaluated the effect of Palbociclib treatment alone and/or in combination with CDDP on FLO-1 (P53 mutant) UGC cell viability, survival, and cell cycle progression, respectviely. The MTT cell viability assay and Compusyn mediated median effect plot analysis (MEPA)(Chou and Talaly) were used to determine synergistic drug combinations of Palbociclib and CDDP in FLO-1 UGC cells. Results: The cell viability data and MEPA indicated that Palbociclib and CDDP show significant synergistic anticancer activity in FLO-1 UGC cells at a ratio of 1:2 and 1:3, respectively. The clonogenic cell survival assay data showed that in comparison to treatment with Palbociclib (0.5µM) or CDDP (1.0 and 1.5µM) alone, the combination treatments (Palbociclib:CDDP) at a ratio of 1:2 and 1:3 exhibited significantly elevated (p<0.05) inhibition of cellular survival in FLO-1 UGC cell lines. In addition, the Combination Index (CI) values of 0.66 and 0.71 for the aforementioned combination ratios suggests a strong synergism between the two drugs. Furthermore, the cell cycle data exhibited a marked increase (p<0.05) in the percentage of FLO-1 cells in the sub-G1-phase (cell death) after treatment with Palbocicb and CDDP combinations for 72 hrs., respectively . Conclusions: Our in vitro data indicate that Palbociclib, as a single agent, is an effective therapeutic strategy for inhibiting UGC cells. Additionally, Palbociclib in combination with CDDP synergistically enhances the anti-tumor activity of CDDP against P53 mutant UGC cells[MM1] . The observed synergism can potentially translate into reduced individual drug dosages and toxicity for Palbociclib and/or CDDP when used in combination. Citation Format: Dhvanir Kansara, Amruta Samant, Priya Pancholi, Tanvi Visal, Shraddha Patel, Vikas Sehdev. Palbociclib synergistically enhances the anticancer activity of cisplatin in P53 mutant model of upper gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5805.
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