Kenjiro Sawada

PI3K/mTOR Dual Inhibitor GSK458 and Arsenic Trioxide Exert Synergistic Antitumor Effects against Ovarian Clear-Cell Carcinoma

Abstract Ovarian clear-cell carcinoma (OCCC), particularly advanced or recurrent settings, is generally resistant to platinum-based chemotherapy, warranting novel therapeutic strategies. Mutations in the PI3K/AKT/mTOR pathway are frequently reported in OCCC. Therefore, we hypothesized that the PI3K/mTOR dual inhibitor, GSK458, and arsenic trioxide (As2O3) may exert synergistic antitumor effects on OCCC. We investigated the effects of GSK458, As2O3, and the combination of GSK458 and As2O3 on cell viability, colony formation, and apoptosis in seven OCCC cells. Mechanistically, transcriptomic differences were assessed among the groups. Additionally, their antitumor effects were evaluated on the three-dimensional cultures of OCCC patient-derived xenografts as well as in vivo. Low-dose combination of GSK458 and As2O3 exerted synergistic antitumor effects in vitro. Viability of the three-dimensional OCCC patient-derived xenograft cultures treated with the combination of GSK458 and As2O3 decreased to 23.8% of that of the control. RNA sequencing revealed that the mechanism was associated with cell cycle and DNA damage repair. The combination of GSK458 and As2O3 synergistically inhibited the PI3K/AKT/mTOR pathway and angiogenesis and increased apoptosis. Compared with any monotherapy, the combination treatment significantly suppressed tumor growth in vivo, thereby enhancing survival. Overall, our findings highlight the potential of the novel combination of GSK458 and As2O3 for OCCC treatment.

Continuous Administration of Anti-VEGFA Antibody Upregulates PAI-1 Secretion from Ovarian Cancer Cells via miR-143-3p Downregulation

Abstract Although bevacizumab (BEV) plays a key role in ovarian cancer treatment, BEV resistance is often observed in clinical settings. This study aimed to identify the genes responsible for BEV resistance. C57BL/6 mice inoculated with ID-8 murine ovarian cancer cells were treated with anti-VEGFA antibody or IgG (control) twice weekly for 4 weeks. The mice were sacrificed, then, RNA was extracted from the disseminated tumors. qRT-PCR assays were performed to identify angiogenesis-related genes and miRNAs that were altered by anti-VEGFA treatment. SERPINE1/PAI-1 was found to be upregulated during BEV treatment. Therefore, we focused on miRNAs to elucidate the mechanism underlying the upregulation of PAI-1 during BEV treatment. Kaplan–Meier plotter analysis revealed that higher expression levels of SERPINE1/PAI-1 were associated with poor prognoses among BEV-treated patients, suggesting that SERPINE1/PAI may be involved in the acquisition of BEV resistance. miRNA microarray analysis followed by in silico and functional assays revealed that miR-143-3p targeted SERPINE1 and negatively regulated PAI-1 expression. The transfection of miR-143-3p suppressed PAI-1 secretion from ovarian cancer cells and inhibited in vitro angiogenesis in HUVECs. Next, miR-143-3p-overexpressing ES2 cells were intraperitoneally injected into BALB/c nude mice. ES2-miR-143-3p cells downregulated PAI-1 production, attenuated angiogenesis, and significantly inhibited intraperitoneal tumor growth following treatment with anti-VEGFA antibody. Continuous anti-VEGFA treatment downregulated miR-143-3p expression, which upregulated PAI-1 and activated an alternative angiogenic pathway in ovarian cancer. In conclusion, the substitution of this miRNA during BEV treatment may help overcome BEV resistance, and this may be used as a novel treatment strategy in clinical settings. Implications: Continuous administration of VEGFA antibody upregulates SERPINE1/PAI-1 expression via the downregulation of miR-143-3p, which contributes to acquiring bevacizumab resistance in ovarian cancer.

Pathophysiological Role and Potential Therapeutic Exploitation of Exosomes in Ovarian Cancer

Exosomes are extracellular vesicles involved in several biological and pathological molecules and can carry many bioactive materials to target cells. They work as important mediators of cell-cell communication and play essential roles in many diseases, especially in cancer. Ovarian cancer is one of the most common gynecological malignancies. Most patients are diagnosed at advanced stages involving widespread peritoneal dissemination, resulting in poor prognosis. Emerging evidence has shown that exosomes play vital roles throughout the progression of ovarian cancer. Moreover, the development of engineered exosome-based therapeutic applications— including drug delivery systems, biomolecular targets and immune therapy—has increased drastically. Herein, we review the functional features of exosomes in ovarian cancer progression and the therapeutic application potential of exosomes as novel cancer treatments.