Inhibition of insulin-like growth factor 1 signaling synergistically enhances the tumor suppressive role of triptolide in triple-negative breast cancer cells.

Abstract

Triptolide (TPL) is an active extract from a Chinese herb, which has been used for centuries in China. TPL exhibits numerous bioactivities and pharmacological effects, including antitumor, anti-inflammatory and immunosuppressive activities. However, previous studies have further revealed a multi-target toxicity of TPL, including reproductive toxicity, hepatotoxicity and renal cytotoxicity. To validate the clinical benefit and reduce the risk of TPL application, studies have investigated the combination of TPL with other reagents to allow lower doses and decrease toxicity. The present study reported that TPL and the insulin-like growth factor-1 receptor (IGF1R) inhibitor AG1024synergistically inhibited cell proliferation and induced apoptosis in triple-negative breast cancer cells. Overexpression of B-cell lymphoma 2 partially reversed the TPL and AG1024-induced increase in apoptosis. A similar synergistic effect was observed with a combination of AG1024 and cisplatin, a DNA damage inducer, in MDA-MB-231 cells. These results suggested that inhibition of IGF1R may sensitize triple-negative breast cancer cells to DNA damage inducers. Using publicly available data from The Cancer Genome Atlas, an amplification and gain of copy number of IGF1R was observed in 38% of triple-negative breast tumors (n=82), 26% of estrogen receptor (ER)-negative tumors (n=174) and 10% of ER-positive tumors (n=594). Similarly, a higher alteration frequency of IGF1R was identified in basal-like breast tumors compared with luminal A/B-like breast tumors. Overexpressed proteins associated with these alterations were revealed to be significantly enriched in multiple oncogenic signaling pathways, key transcription factor networks and DNA repair pathways. In summary, the present study suggested that inhibition of IGFR signaling and induction of DNA damage may exhibit synergistic effects for the treatment of triple-negative and ER-negative breast cancer.