Abstract
Recent studies have revealed that antiparasitic agents showed promising inhibitory effects on tumors, raising a possibility that repositioning this class of drugs may shed new light on clinical therapy against tumors. CWHM-1008 is a novel class of antimalarial drug; however, the inhibitory impact of CWHM-1008 on lung adenocarcinoma (LUAD) cells remains unclear. This study aimed to explore the anticancer effect and underlying mechanisms of CWHM-1008 on LUAD cells in vitro and in vivo. Human LUAD cells, H358 and A549, were treated with varying concentrations of CWHM-1008 at different lengths of time. Cell viability, colony formation, cell count, flow cytometry findings, microtubule-associated protein-1 light chain 3-green- (LC3-) GFP/RFP adenovirus infection status, and the expression of apoptosis and autophagy-related proteins were examined. Potential effects of an autophagy inhibitor (LY294002) and constitutively active Akt plasmid (CA-Akt) on CWHM-1008-induced apoptosis were also examined. Our results showed that CWHM-1008 significantly inhibited proliferation, induced apoptosis, and enhanced autophagy flux by blocking the RAC-alpha serine/threonine-protein kinase/the mammalian target of rapamycin (Akt/mTOR) axis in two LUAD cells. In addition, autophagy inhibited by LY294002 or CA-Akt transfection accelerated CWHM-1008-induced apoptosis in those LUAD cells. Moreover, CWHM-1008 significantly inhibited the growth and induced apoptosis of A549 cell in nude mice in vivo. The present findings provide new insights into anticancer properties of CWHM-1008, suggesting that it may be an adjuvant treatment for LUAD treatment, warranting further study.
Highlights
Lung cancer is associated with the highest incidence (11.6%) and mortality (18.4%) rates of all cancer types among both men and women worldwide; approximately 2.1 million patients develop this condition, and 1.8 million die from it annually [1]
Dulbecco’s modified eagle medium (DMEM) and Roswell Park Memorial Institute 1640 (RPMI 1640) medium, fetal bovine serum (FBS), and trypsin were purchased from HyClone (Buckinghamshire, UK). e bicinchoninic acid (BCA) protein assay kit, Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL), dimethyl sulfoxide, penicillin-streptomycin, propidium iodide (PI), and APC-Annexin V were obtained from Beyotime (Shanghai, China). e rabbit anti-human Ki-67 monoclonal antibody was purchased from abcarta (Suzhou, China)
It has previously been reported that phosphorylated Akt/mTOR plays an important role as a negative modulator in autophagy activation [28]; we investigated whether the Akt/ mTOR pathway is associated with CWHM-1008-induced autophagy
Summary
Lung cancer is associated with the highest incidence (11.6%) and mortality (18.4%) rates of all cancer types among both men and women worldwide; approximately 2.1 million patients develop this condition, and 1.8 million die from it annually [1]. Chemotherapy, targeted therapy, and immunotherapy, among other strategies, have been proposed to improve survival outcomes of LUAD [3,4,5], drug resistance, recurrence, and metastasis are associated with poor prognosis and high rates of treatment failure [6], resulting in 5year survival rates of
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