Inhibition of STAT3/VEGF/CDK2 axis signaling is critically involved in the antiangiogenic and apoptotic effects of arsenic herbal mixture PROS in non-small lung cancer cells.

Hyemin Lee,Sung-Hoon Kim,Hyo-Jung Lee,Ill Ju Bae,Jeong Jin Kim

doi:10.18632/oncotarget.21973

Hyemin Lee, Sung-Hoon Kim + Show 3 more

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https://doi.org/10.18632/oncotarget.21973

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Journal: Oncotarget	Publication Date: Oct 19, 2017
Citations: 13	License type: cc-by

Affiliation: Kyung Hee University

Abstract

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.

Highlights

Lung cancer is the most common cause of cancer related deaths and its main primary types are small lung cancer (10~15%) and non-small lung cancer (85~90%) worldwide [1, 2]
These findings suggest that PROS exerts antiangiogenic and apoptotic effects via inhibition of signal transducer and activator of transcription 3 (STAT3)/ vascular endothelial growth factor (VEGF)/ cyclindependent kinase 2 (CDK2) axis signaling as a potent anticancer agent for lung cancer treatment
PROS exerted significant cytotoxicity in several cancers such as A549, H460, HCT-116, 786-O, PC-3 and DU145 cancers compared to OS or PR alone, while PR showed weaker cytotoxicity in A549 and H460 non-small cell lung cancer cells (NSCLCs) compared to other cancers

Summary

Introduction

Lung cancer is the most common cause of cancer related deaths and its main primary types are small lung cancer (10~15%) and non-small lung cancer (85~90%) worldwide [1, 2]. The treatment for lung cancer is surgery, chemotherapy, radiotherapy, immunotherapy and targeted therapy mainly for EGFR, VEGF, ALK and NF-κB [3, 4]. It is well documented that arsenic trioxide (As2O3) exerts antitumor effect in several cancers including leukemia [5], breast cancer [6], prostate cancer [7], lung cancer [8], cervical cancer [9], gastric cancer [10, 11], pancreatic cancer [12], hepatocellular cancer [13] and glioblastoma [14]. Tetraarsenic hexoxide(As4O6) showed antitumor effect more effectively than arsenic trioxide in HPV 16-positive SiHa cervical cancer [16] and enhanced radiation sensitivity to reduce the growth of Meth-A induced fibrosarcoma and nasopharyngeal squamous cancer implanted in Balb/c nu/nu mice [17]. As known as anticancer herbal medicines, Oldenlandia diffusa is known to have anticancer [28], antioxidant [29], anti-inflammatory [30] and immunomodulatory [31] and Salvia miltiorrhiza has www.impactjournals.com/oncotarget anti-inflammatory [32], antioxidant [33] and anti-cancer activity [34] with constituents of diterpene quinone, tanshinoneI, tanshinone II cryptotanshinone, and miltirone [35]

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