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Sci Rep ; 7(1): 13749, 2017 10 23.
Article in English | MEDLINE | ID: mdl-29062040

ABSTRACT

Induction of premature senescence represents a novel functional strategy to curb the uncontrolled proliferation of malignant cancer cells. This study unveils the regiospecific synthesis of novel isoxazoline derivatives condensed to ring A of medicinal plant product Withaferin-A. Intriguingly, the cis fused products with ß-oriented hydrogen exhibited excellent cytotoxic activities against proliferating human breast cancer MCF7 and colorectal cancer HCT-116 cells. The most potent derivative W-2b triggered premature senescence along with increase in senescence-associated ß-galactosidase activity, G2/M cell cycle arrest, and induction of senescence-specific marker p21Waf1/Cip1 at its sub-toxic concentration. W-2b conferred a robust increase in phosphorylation of mammalian checkpoint kinase-2 (Chk2) in cancer cells in a dose-dependent manner. Silencing of endogenous Chk2 by siRNA divulged that the amplification of p21 expression and senescence by W-2b was Chk2-dependent. Chk2 activation (either by ectopic overexpression or through treatment with W-2b) suppressed NM23-H1 signaling axis involved in cancer cell proliferation. Finally, W-2b showed excellent in vivo efficacy with 83.8% inhibition of tumor growth at a dose of 25 mg/kg, b.w. in mouse mammary carcinoma model. Our study claims that W-2b could be a potential candidate to limit aberrant cellular proliferation rendering promising improvement in the treatment regime in cancer patients.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cellular Senescence/drug effects , Isoxazoles/pharmacology , Withanolides/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis , Breast Neoplasms/metabolism , Cell Cycle , Cell Proliferation , Checkpoint Kinase 2/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Isoxazoles/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Signal Transduction , Tumor Cells, Cultured , Withanolides/chemistry , Xenograft Model Antitumor Assays
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