Novel ABCG2 Antagonists Reverse Topotecan-Mediated Chemotherapeutic Resistance in Ovarian Carcinoma Xenografts

Abstract

Chemotherapeutic resistance remains a challenge in the treatment of ovarian carcinoma, especially in recurrent disease. Despite the fact that most patients with newly diagnosed tumors attain complete remission following cytoreductive surgery and chemotherapy, ovarian carcinoma has a recurrence rate that exceeds 75%. The ATP Binding Cassette family G member 2 (ABCG2) efflux protein has been described as one mechanism that confers multiple drug resistance (MDR) to solid tumors and contributes to topotecan (TPT) resistance in ovarian carcinoma. In fact, one clinical trial demonstrated ABCG2 expression in all patients with primary or recurrent ovarian carcinoma. On the basis of our previous work, we hypothesized that three compounds (CID44640177, CID1434724, and CID46245505), which represent a new piperazine-substituted pyrazolo[1,5]pyrimidine substructure class of ABCG2-specific antagonists, would restore chemosensitivity to drug-resistant ovarian cancer in vitro and in vivo. In order to address the treatment difficulties associated with chemotherapeutic resistance in ovarian cancer, we combined each compound (CID44640177, CID1434724, and CID46245505) with TPT and administered the mixture to chemoresistant Igrov1/T8 ovarian cancer cells in vitro and Igrov1/T8 xenografts in CB-17 SCID mice. We found that only nanomolar concentrations of each ABCG2-inhibitor in combination with TPT were required to restore chemosensitivity to Igrov1/T8 cells in vitro. In vivo, substantial tumor reduction was achieved with each compound in 4 days, with CID1434724 causing the largest reduction in excess of 60%. No signs of secondary toxic effects were observed with the ABCG2 antagonists. These novel compounds should be viewed as promising drug candidates to reverse ABCG2-mediated chemoresistance.

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

“…However, the efficacy and safety of these compounds in humans remain unclear, because, to our knowledge, their safety in humans has not been demonstrated in clinical studies. The similar problem is also the case for the new ABCG2 inhibitors developed recently (Juvale and Wiese, 2015; Ricci et al, 2016). Therefore, we aimed to identify a solution by exploring new promising agents for ABCG2 regulation from drugs currently available on the market.…”

Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer

“…Despite effectiveness of the first-line carboplatin and paclitaxel regimen, the majority of ovarian cancer patients die because they develop chemoresistant disease (36,37). Numerous receptors and pathways are known to be critical in ovarian cancer chemoresistance (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51), but no targeted agent has been shown to enhance sensitivity to both carboplatin and paclitaxel. Here, we present several lines of evidence that AXL has a critical role in resistance to paclitaxel and carboplatin.…”

Shikonin Enhances the Antitumor Effect of Cabazitaxel in Prostate Cancer Stem Cells and Reverses Cabazitaxel Resistance by Inhibiting the Expression of ABCG2 and ALDH3A1

“…The ABCG2 + cancer cells initially called side population cells based on ow cytometry results, which can e ux most agents and prevent treatment success [12]. Inhibition of ABCG2 increased the chemotherapeutic agents' sensitivity in breast cancer cells [41], and ovarian carcinoma cells [42].…”