Abstract 2035: A Benzenesulfornamide with potential to improve chemoresponse of ovarian cancer through activation of AMPK and immunogenic cell death

Abstract Introduction: Ovarian cancer is a leading cause of death among women globally often characterized by poor prognosis and aggressive tumor growth. The therapeutic outcomes of ovarian cancer patients are limited by the development of acquired chemoresistance and the lack of targeted therapies. This study aimed to understand the mechanism in which a benzenesulfornamide named Y3 enhances the efficacy of chemotherapeutic agents. Y3 was previously identified by our team as an activator of AMPK with the activity to induce immunogenic cell death of ovarian cancer cells. Material and Methods: Patient-derived ovarian cancer cell lines were pretreated with Y3 for 3 h before treatment of carboplatin or paclitaxel. Celltiter Glo assay was performed to determine the impact of Y3 pretreatment on the IC50 values of carboplatin or paclitaxel after 48 h. Apoptosis was evaluated using Annexin VI/PI staining and Caspase 3 activity assays. The role of AMPK pathway was assessed using AMPK siRNAs and western blot. The potential of Y3 to enhance immunogenic cell death induced by carboplatin or paclitaxel was evaluated in a syngeneic mouse model of ovarian cancer using a vaccination assay. The control group mice were vaccinated by subcutaneously injecting mouse ovarian cancer cells treated by carboplatin in vitro for 24 h into the left flank. The test group mice were vaccinated by injecting Y3-carboplatin co-treated cells. One week after vaccination, untreated live cancer cells were injected into the right flank of both groups. Tumor growth was monitored. Results: Ovarian cancer cell lines pretreated with Y3 showed decreased IC50 values for carboplatin and paclitaxel treatments. The apoptotic cell populations stained by Annexin VI were increased in the Y3 pretreated in comparisons with the single treatment groups. Caspase-3 activity validated the results of Annexin VI/PI staining assay. AMPK knockdown by siRNAs effectively reduced the levels of phospho-AMPK that was induced by Y3, which also dampened the Y3-promoted chemotherapeutic effects on ovarian cancer cells. In the in vivo vaccination assay, tumor growth in the right flank was suppressed in the mice vaccinated with Y3-carboplatin co-treated cells to an extend that is more significant than the control group. Conclusion: Y3 pretreatment increased the sensitivity of ovarian cancer cell lines to carboplatin and paclitaxel. The effects of Y3 on ovarian cancer cells depend on the activation of AMPK. Y3 enhances the immunogenicity of carboplatin-treated ovarian cancer cells. Citation Format: Juhyun Kim, Nia Montero, Shefali Sharma, Miranda Mansolf, Kevin Yang, Tobias Hartwich, Yang Yang-Hartwich. A Benzenesulfornamide with potential to improve chemoresponse of ovarian cancer through activation of AMPK and immunogenic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2035.