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Molecules 2016, 21(12), 1758; doi:10.3390/molecules21121758

Cryptolepine, a Plant Alkaloid, Inhibits the Growth of Non-Melanoma Skin Cancer Cells through Inhibition of Topoisomerase and Induction of DNA Damage

1
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
2
Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA
3
Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
4
Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 17 November 2016 / Revised: 13 December 2016 / Accepted: 17 December 2016 / Published: 21 December 2016
(This article belongs to the Special Issue Cancer Chemoprevention)
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Abstract

Topoisomerases have been shown to have roles in cancer progression. Here, we have examined the effect of cryptolepine, a plant alkaloid, on the growth of human non-melanoma skin cancer cells (NMSCC) and underlying mechanism of action. For this purpose SCC-13 and A431 cell lines were used as an in vitro model. Our study reveals that SCC-13 and A431 cells express higher levels as well as activity of topoisomerase (Topo I and Topo II) compared with normal human epidermal keratinocytes. Treatment of NMSCC with cryptolepine (2.5, 5.0 and 7.5 µM) for 24 h resulted in marked decrease in topoisomerase activity, which was associated with substantial DNA damage as detected by the comet assay. Cryptolepine induced DNA damage resulted in: (i) an increase in the phosphorylation of ATM/ATR, BRCA1, Chk1/Chk2 and γH2AX; (ii) activation of p53 signaling cascade, including enhanced protein expressions of p16 and p21; (iii) downregulation of cyclin-dependent kinases, cyclin D1, cyclin A, cyclin E and proteins involved in cell division (e.g., Cdc25a and Cdc25b) leading to cell cycle arrest at S-phase; and (iv) mitochondrial membrane potential was disrupted and cytochrome c released. These changes in NMSCC by cryptolepine resulted in significant reduction in cell viability, colony formation and increase in apoptotic cell death. View Full-Text
Keywords: cryptolepine; skin cancer; topoisomerase; DNA damage; cell cycle; apoptosis cryptolepine; skin cancer; topoisomerase; DNA damage; cell cycle; apoptosis
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Pal, H.C.; Katiyar, S.K. Cryptolepine, a Plant Alkaloid, Inhibits the Growth of Non-Melanoma Skin Cancer Cells through Inhibition of Topoisomerase and Induction of DNA Damage. Molecules 2016, 21, 1758.

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