A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin

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 cellsand suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.

Cisplatin for cancer therapy and overcoming chemoresistance

“…The HIPEC model that was adapted could forecast the bioactive utilisation of cisplatin by regression analysis [160]. Cisplatin combined with the taxanes is another chemotherapeutic regimen in attenuating OC, but its efficacy is reduced by chemoresistance of the OC cells [101]. LLL12B is a small molecule inhibitor of chemoresistance that showed improved sensitivity when administered in combination with both cisplatin and paclitaxel together compared to either cisplatin or paclitaxel alone [101].…”

“…Cisplatin combined with the taxanes is another chemotherapeutic regimen in attenuating OC, but its efficacy is reduced by chemoresistance of the OC cells [101]. LLL12B is a small molecule inhibitor of chemoresistance that showed improved sensitivity when administered in combination with both cisplatin and paclitaxel together compared to either cisplatin or paclitaxel alone [101]. It suppressed cell viability and proliferation by downregulating the signal transducer and activator of transcription-3 (STAT3) pathway [101].…”