Despite the antitumor effects of asrsenic trioxide (
As2O3), tetraarsenic hexoxide (
As4O6 or PR) and
tetraarsenic tetrasulfide (As4S4) in several
cancers, their adverse
poisoning, toxicity and resistance are still hot issues for effective
cancer therapy. Here, antitumor mechanism of
arsenic herbal mixture PROS including PR and OS (Oldenlandia diffusa and Salvia miltiorrhiza extract) was elucidated in
non-small cell lung cancer cells (NSCLCs), since PR alone showed resistant cytotoxicity in NSCLCs compared to other
cancers. PROS exerted significant cytotoxicity, induced sub-G1 phase and S phase arrest, increased apoptotic bodies, and attenuated the expression of pro-PARP, Bcl-2,
Cyclin E,
Cyclin A, CDK2, E2F1, p-Src, p-STAT3, p-ERK, p-AKT, COX-2 and SOCS-1 in A549 and H460 cells along with disrupted binding of STAT3 with CDK2 or
VEGF. Notably, PROS inhibited
VEGF induced proliferation, migration and tube formation in HUVECs and suppressed angiogenesis in chorioallantoic membrane (CAM) assay via reduced phosphorylation of VEGFR2, Src and STAT3. Consistently, PROS reduced the growth of H460 cells implanted in BALB/c athymic nude mice via inhibition of STAT3, and
VEGF and activation of
caspase 3. Overall, these findings suggest that PROS exerts antiangiogenic and apoptotic effects via inhibition of STAT3/
VEGF/ CDK2 axis signaling as a potent
anticancer agent for
lung cancer treatment.