Anti‐growth and pro‐apoptotic effects of dasatinib on human oral cancer cells through multi‐targeted mechanisms

Abstract

Dasatinib is an inhibitor of Src that has anti‐tumour effects on many haematological and solid cancers. However, the anti‐tumour effects of dasatinib on human oral cancers remain unclear. In this study, we investigated the effects of dasatinib on different types of human oral cancer cells: the non‐tumorigenic YD‐8 and YD‐38 and the tumorigenic YD‐10B and HSC‐3 cells. Strikingly, dasatinib at 10 µM strongly suppressed the growth and induced apoptosis of YD‐38 cells and inhibited the phosphorylation of Src, EGFR, STAT‐3, STAT‐5, PKB and ERK‐1/2. In contrast, knockdown of Src blocked the phosphorylation of EGFR, STAT‐5, PKB and ERK‐1/2, but not STAT‐3, in YD‐38 cells. Dasatinib induced activation of the intrinsic caspase pathway, which was inhibited by z‐VAD‐fmk, a pan‐caspase inhibitor. Dasatinib also decreased Mcl‐1 expression and S6 phosphorylation while increased GRP78 expression and eIF‐2α phosphorylation in YD‐38 cells. In addition, to its direct effects on YD‐38 cells, dasatinib also exhibited anti‐angiogenic properties. Dasatinib‐treated YD‐38 or HUVEC showed reduced HIF‐1α expression and stability. Dasatinib alone or conditioned media from dasatinib‐treated YD‐38 cells inhibited HUVEC tube formation on Matrigel without affecting HUVEC viability. Importantly, dasatinib's anti‐growth, anti‐angiogenic and pro‐apoptotic effects were additionally seen in tumorigenic HSC‐3 cells. Together, these results demonstrate that dasatinib has strong anti‐growth, anti‐angiogenic and pro‐apoptotic effects on human oral cancer cells, which are mediated through the regulation of multiple targets, including Src, EGFR, STAT‐3, STAT‐5, PKB, ERK‐1/2, S6, eIF‐2α, GRP78, caspase‐9/3, Mcl‐1 and HIF‐1α.

FYN: emerging biological roles and potential therapeutic targets in cancer

“…Chemotherapy combined with dasatinib is also significantly more effective in treating tumors than chemotherapy alone [159][160][161]. As a result of its inhibition of multiple targets, dasatinib produces anti-growth, anti-angiogenic, and pro-apoptotic effects in oral cancer [162]. Dasatinib has also been shown to be effective in breast cancer [163,164].…”

“…Currently, multiple clinical trials are underway to evaluate inhibitors of FYN/SRC, which not only improve chemotherapy efficacy, [159][160][161]174], but also significantly enhance the therapeutic response to immunotherapy and radiotherapy [157,158]. A variety of preclinical studies have also demonstrated that FYN/SRC inhibitors inhibit multiple tumor progressions [155,156,162,166,175]. Hence, in order to better understand the activation and inactivation of FYN, as well as the regulation of FYN expression in additional molecules, future studies are needed.…”

Dasatinib regulates the proliferation and osteogenic differentiation of PDLSCs through Erk and EID3 signals

“…The present results showed that a high concentration of dasatinib significantly inhibited the phosphorylation of Erk, which may be one of the mechanisms by which dasatinib inhibits the proliferative activity of PDLSCs. Similarly, several studies have revealed the inhibitory effects of dasatinib on the MAPK/Erk pathway in some types of cancer cells and MSCs [18,[29][30][31]. However, single use of dasatinib was also reported to promote the activation of MAPK/Erk signaling pathways in melanocytes [32], or have no effects on MAPK/Erk in nonclear cell renal cell carcinoma [33].…”

Targeting the FAK-Src Complex in Desmoplastic Small Round Cell Tumors, Ewing Sarcoma, and Rhabdomyosarcoma

“…The in vivo results revealed that the combination treatment does not show superior effects compared to dasatinib single-agent treatment as shown in vitro . The superior in vivo effect of dasatinib could potentially be explained by the anti-angiogenic properties of dasatinib [ 44 ].…”