Abstract
Ovarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin-paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cells and suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.
Highlights
Ovarian cancer is the most lethal gynecologic malignancy [1, 2]
Compared with those treated by dimethyl sulfoxide (DMSO), p-Signal Transducer and Activator of Transcription 3 (STAT3) was inhibited by LLL12B (Fig 2A)
LLL12B inhibited STAT3 phosphorylation and down-regulated downstream target genes which are associated with cancer cell proliferation and growth [23,24,25,26]
Summary
Ovarian cancer is the most lethal gynecologic malignancy [1, 2]. In 2018, there were approximately 22,240 new cases and 14,070 deaths from ovarian cancer in the United States [3]. A novel small molecule targets STAT3 in ovarian cancer cells. Adjuvant chemotherapy is usually needed following surgical cytoreduction. Platinum in combination with taxane chemotherapy is considered a first-line approach [4, 5]. Many research efforts focus upon reversal of chemotherapy resistance for recurrent disease, but less attention is given to enhancing sensitivity to chemotherapy during the primary treatment of ovarian cancer [8,9,10,11]
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