| In vitro: |
| J Nat Prod. 1993 Oct;56(10):1831-4. | | Two bioactive pterocarpans from Erythrina burana.[Pubmed: 8277323] |
METHODS AND RESULTS:
Bioactivity-directed fractionation of the CHCl3 extract of the bark of Erythrina burana afforded phaseollidin [1] and cristacarpin [2]. Both 1 and cristacarpin exhibited moderate but selective activity towards DNA repair-deficient yeast mutants, whereas only 1 was found to be cytotoxic. 13C-nmr spectra of both compounds were assigned. | | Age (Dordr). 2016 Jun;38(3):62. | | Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21(waf-1).[Pubmed: 27246693 ] | Stress-induced premature senescence (SIPS) is quite similar to replicative senescence that is committed by cells exposed to various stress conditions viz. ultraviolet radiation (DNA damage), hydrogen peroxide (oxidative stress), chemotherapeutic agents (cytotoxic threat), etc.
METHODS AND RESULTS:
Here, we report that Cristacarpin, a natural product obtained from the stem bark of Erythrina suberosa, promotes endoplasmic reticulum (ER) stress, leading to sub-lethal reactive oxygen species (ROS) generation and which eventually terminates by triggering senescence in pancreatic and breast cancer cells through blocking the cell cycle in the G1 phase. The majority of Cristacarpin-treated cells responded to conventional SA-β-gal stains; showed characteristic p21(waf1) upregulation along with enlarged and flattened morphology; and increased volume, granularity, and formation of heterochromatin foci-all of these features are the hallmarks of senescence. Inhibition of ROS generation by N-acetyl-L-cysteine (NAC) significantly reduced the expression of p21(waf1), confirming that the modulation in p21(waf1) by anti-proliferative Cristacarpin was ROS dependent. Further, the elevation in p21(waf1) expression in PANC-1 and MCF-7 cells was consistent with the decrease in the expression of Cdk-2 and cyclinD1.
CONCLUSIONS:
Here, we provide evidence that Cristacarpin promotes senescence in a p53-independent manner. Moreover, Cristacarpin treatment induced p38MAPK, indicating the ROS-dependent activation of the MAP kinase pathway, and thus abrogates the tumor growth in mouse allograft tumor model. |
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