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Regiospecific Synthesis of Ring A Fused Withaferin A Isoxazoline Analogues: Induction of Premature Senescence by W-2b in Proliferating Cancer Cells.
- Source :
-
Scientific reports [Sci Rep] 2017 Oct 23; Vol. 7 (1), pp. 13749. Date of Electronic Publication: 2017 Oct 23. - Publication Year :
- 2017
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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 β-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 β-galactosidase activity, G2/M cell cycle arrest, and induction of senescence-specific marker p21 <superscript>Waf1/Cip1</superscript> 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.
- Subjects :
- 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
Antineoplastic Agents pharmacology
Breast Neoplasms drug therapy
Breast Neoplasms pathology
Cellular Senescence drug effects
Isoxazoles pharmacology
Withanolides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 29062040
- Full Text :
- https://doi.org/10.1038/s41598-017-13664-x