title: Cytotoxicity of withasteroids: withametelin induces cell cycle arrest at G2/M phase and mitochondria-mediated apoptosis in non-small cell lung cancer A549 cells.
abstract: Considerable interest has been gained by withasteroids because of their structural uniqueness and wide spectrum of biological activities. However, limited systematic studies for proving their cytotoxic potential have so far been reported. Hence, an attempt was made to test the cytotoxicity of six withasteroids viz., withametelin (WM), withaphysalin D, withaphysalin E, 12-deoxywithastramonolide, Withaperuvin B, and physalolactone against A549, HT-29, and MDA-MB-231 cancer cell lines. Significant cytotoxic effect of WM against A549 cells (IC50value of 6.0 μM), MDA-MB-231 cells (IC50value of 7.6 μM), and HT-29 cells (IC50value of 8.2 μM) was observed. Withaperuvin B and physalolactone were found to be effective against MDA-MB-231 cells. The significantly active WM arrested the A549 cells at G2/M phase and downregulated the expression of G2/M regulatory proteins such as cdc2, cyclin B1, and cdc25C. Apoptosis induced by WM in A549 cells was associated with the generation of ROS and depletion of MMP. Furthermore, WM treatment resulted in Bax upregulation, Bcl-2 downregulation, translocation of cytochrome c to mitochondria, activation of caspase-9 and -3, and PARP cleavage corroborating the apoptosis induction through intrinsic apoptotic pathway. Thus, WM possessing broader cytotoxic effect is a promising lead molecule which has the potential to be developed as a new therapeutic agent for NSCLC.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology and Science - Pilani Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, Hyderabad, Telangana State, 500078, India.
authors.forename: Poorna Chandra
authors.initials: PC
authors.lastname: Rao
authors.affiliation: Department of Pharmacy, Birla Institute of Technology and Science - Pilani Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, Hyderabad, Telangana State, 500078, India. sajeli@hyderabad.bits-pilani.ac.in.
authors.forename: Sajeli
authors.initials: S
authors.lastname: Begum
authors.affiliation: Medicinal Plants Processing Research Center, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Mohammad Ali Farboodniay
authors.initials: MA
authors.lastname: Jahromi
authors.affiliation: Biology Division, Shahed 15 Education Center, Shiraz, Iran.
authors.forename: Zahra Hosseini
authors.initials: ZH
authors.lastname: Jahromi
authors.affiliation: Biological Research Department, Incozen Therapeutics Pvt Ltd, Alexandria Knowledge Park, Turakapally, Hyderabad, Telangana State, India.
authors.forename: Saketh
authors.initials: S
authors.lastname: Sriram
authors.affiliation: Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Sahai
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D010840:Phytosterols / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D007783:Lactones; D010840:Phytosterols; D017382:Reactive Oxygen Species
keywords: Apoptosis; Cytotoxicity; Lung cancer; ROS; Withametelin; Withasteroids