The Antiparasitic Drug, Potassium Antimony Tartrate, Inhibits Tumor Angiogenesis and Tumor Growth in Nonsmall-Cell Lung Cancer

Abstract

Repurposing existing drugs not only accelerates drug discovery but rapidly advances clinical therapeutic strategies. In this article, we identified potassium antimonyl tartrate (PAT), an antiparasitic drug, as a novel agent to block angiogenesis by screening US Food and Drug Administration-approved chemical drugs. By comparing the cytotoxicity of PAT in various nonsmallcell lung cancer (NSCLC) cells with that observed in primary cultured human umbilical vein endothelial cells (HUVECs), we found that HUVECs were much more sensitive to the PAT treatment. In in vivo tumor xenograft mouse models established either by PAT-resistant A549 cells or by patient primary tumors, PAT significantly decreased the tumor volume and tumor weight of NSCLC xenografts at dosage of 40 mg/kg (i.p., daily) and, more importantly, augmented the antitumor efficacy of cisplatin chemotherapy. Remarkable loss of vascularization in the treated xenografts indicated the in vivo antiangiogenesis property of PAT, which was well correlated with its tumor growth inhibition in NSCLC cells. Furthermore, in the in vitro angiogenic assays, PAT exhibited dose-dependent inhibition of HUVEC proliferation, migration, and tube formation in response to different stimuli. Consistently, PAT also abolished the vascular endothelial cell growth factor-induced angiogenesis in the Matrigel plugs assay. Mechanistically, we found that PAT inhibited the activities of several receptor tyrosine kinases and specifically blocked the activation of downstream Src and focal adhesion kinases in HUVECs. Taken together, our results characterized the novel antiangiogenic and antitumor function of PAT in NSCLC cells. Further study of PAT in anticancer clinical trials may be warranted.

The Antileishmanial Potential of C-3 Functionalized Isobenzofuranones against Leishmania (Leishmania) Infantum Chagasi

“…Conceivably, due to the intense replication of this parasite during acute infection, it could be strongly affected by DNA damage or free radicals. Indeed, reports in the literature have indicated that anti-cancer drugs that affect cellular proliferation can be used as anti-microbial agents because both cell types share common behaviors concerning their high proliferative capabilities [27][28][29]. Indeed, a recent work evidenced the antileishmanial actions of other two isobenzofuranone derivatives and indicated that these actions were due to the induction of reactive oxygen species (ROS)-mediated apoptosis-like cell death and the inhibition of topoisomerases [30].…”

Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents

“…The area under the curve (AUC) and incremental AUC (DAUC, defined as the AUC occurring above the baseline value) were calculated by the trapezoidal rule. Statistical differences between vehicle and single treatment groups or between single and combination treatment groups were determined by one-or two-way analysis of variance followed by Student's t test (Hwee et al, 2015;Wang et al, 2015), unless otherwise indicated in figure legends. Statistical analyses were performed using a SAS-based system (SAS Institute, Cary, NC) or Prism software (GraphPad Software, San Diego, CA).…”

Identification of cisplatin sensitizers through high-throughput combinatorial screening

“…It has been reported that PAT may induce the caspase-and reactive oxygen species (ROS)-dependent apoptosis of human myeloid leukemia HL-60 cells and lymphoid tumor cells (39,40). Of note, a recent study reported that PAT exerted anti-angiogenic effects on lung cancer (41). The present study revealed the significant ability of PAT to enhance the anticancer activity of CDDP in a synergistic manner, suggesting that this drug may potentially be used in combination with CDDP to improve the therapeutic efficacy.…”