Abstract 1009: Combination Niraparib and Metformin synergistically inhibits endometrial cancer cell growth and metastasis

Abstract

Backgroud Endometrial Carcinoma (EC) is the most common gynecological malignancy among women. Even with a favorable prognosis, cure is still elusive with recurrence, chemotherapy resistance and poor outcome. Poly ADP-ribose polymerase inhibitors (PARPi) have been emerged as promising cancer therapeutics, especially for tumors with deficient homologous recombination (HR) repair. Niraparib for example is well established for ovarian cancer. Metformin, an antidiabetic drug, has been reported to be a new adjunctive strategy for different cancer types, including endometrial cancer. While the effect of Niraparib for EC as monotherapy or in combination with Metformin is still unknown. Method Here we used two types of endometrial cancer cell lines Ishikawa and HEC-1B to detect the effect of Niraparib as monotherapy or in combination with Metformin on cell proliferation, apoptosis, invasion and metastasis. The 50% Inhibitory concentration (IC50) was assessed, and transwell, Annexin V staining, clonogenic assay were applied. Also, western blotting was performed to determine the expression of proteins involved, such as Bax, Caspase-3, Bcl-2, p-AKT, RAD51, γ-H2AX and so on. Results Our study demonstrated that Niraparib inhibited endometrial cell growth in both Ishikawa and HEC-1B cell lines with IC50 0.024umol/L and 0.127umol/L separately. The invasion and metastasis were also suppressed. Annexin V staining showed that Niraparib could significantly promoted apoptosis, which was largely enhanced by Metformin combination therapy (p<0.01). Accordingly, the apoptosis-related proteins Bax, Caspase-3, and DNA damage-related protein RAD51, γ-H2AX were increased, while proliferation-related protein p-AKT, anti-apoptosis-related protein Bcl-2, invasion and metastasis-related protein E-cadherin were decreased, as confirmed by western blotting. Conclusion Niraparib shows the anticancer effect on endometrial cancer cell through inhibiting the cell viability, metastasis and inducing apoptosis, which is significantly enhanced by the combination with Metformin. Our results provide preclinical evidence that the combination of these well-establised drugs may warrant further clinical investigation for endometrial cancer treatment. Citation Format: Qiyu Gan, Jingxin Cheng, Rui Chen, Yachun Bie, Guozeng Wang, Linlin Chang. Combination Niraparib and Metformin synergistically inhibits endometrial cancer cell growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1009.

Small molecule targeted therapies for endometrial cancer: progress, challenges, and opportunities

“…4), a PARPi widely used in the treatment of ovarian cancer, 120 was also investigated by the Chang group regarding the effects of its combination with MET on the growth of EC cells. 121 The results showed that niraparib alone inhibited the growth of Ishikawa and HEC-1B cells (IC 50 values were 0.024 μmol L −1 and 0.127 μmol L −1 , respectively), and effected cell invasion and metastasis. In addition, treatment with niraparib alone induced apoptosis, which could be greatly enhanced by MET .…”