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.

miR‑589‑3p sponged by the lncRNA TINCR inhibits the proliferation, migration and invasion and promotes the apoptosis of breast cancer cells by suppressing the Akt pathway via IGF1R

“…Powell et al ( 52 ) demonstrated that the commonly inherited IGF1R variant (rs2016347) reduces breast cancer risk by enhancing mammary gland involution. In addition, triptolide and IGF1R inhibitor (AG1024) can synergistically inhibit the proliferation and induce the apoptosis of triple-negative breast cancer cells ( 53 ). These studies indicated that IGF1R serve some essential roles in the occurrence and development of breast cancer.…”

Triptolide Inhibits the Biological Processes of HUVECs and HepG2 Cells via the Serine Palmitoyltransferase Long Chain Base Subunit 2/Sphingosine-1-Phosphate Signaling Pathway

“…TP is a small molecule compound with antitumor, antiangiogenic, anti-inflammatory, and proapoptotic properties [13]. It is found that TP exerts strong inhibitory effect on the biological processes of liver [14,15], ovarian [16][17][18][19], lung [20][21][22], gastric [23,24], and breast [25,26] cancer cells.…”

Triptolide Inhibits the Biological Processes of HUVEC and HepG2 Cells via the Serine Palmitoyltransferase Long Chain Base Subunit 2/sphingosine-1-phosphate Signaling Pathway

“…It is a small molecule compound with anti-tumor, anti-angiogenesis, anti-inflammatory and pro-apoptotic effects [8]. TP has anti-cancer effect against liver [9,10], ovarian [11][12][13][14], lung [15][16][17], gastric [18,19], breast [20,21].…”