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.
Highlights
Cryptolepine (Figure 1A) is an alkaloid isolated from the roots of Central and West African shrub Cryptolepis sanguinolenta (Lindl.)
Western blot analysis revealed that basal levels of topoisomerases (Topo I and Topo IIα) were higher in SCC-13 and A431 cells compared to normal human epidermal keratinocytes (NHEK) (Figure 1B)
The gel electrophoresis data indicated that the Topo I and topoisomerase II (Topo II) activity was greater in SCC-13 and A431 cells compared to NHEK
Summary
Cryptolepine (Figure 1A) is an alkaloid isolated from the roots of Central and West African shrub Cryptolepis sanguinolenta (Lindl.). The aqueous extract from the roots of this plants have been traditionally used for the treatment of malaria, rheumatism, urinary tract infections, upper respiratory tract infections and intestinal disorders in Central and West African countries like Ghana and Nigeria [1,2]. Cryptolepine has demonstrated various pharmacological and biological activities including anti-malarial [3], anti-bacterial [4], anti-fungal [5], and anti-hyperglycaemic [6,7]. The anti-inflammatory activity of cryptolepine has been documented in different animal model systems [8,9]. The anti-inflammatory activity of cryptolepine is due to inhibition of COX-2/PGE2 signaling and inhibition of other promotors of inflammation including TNFα and iNOS [8,9,10,11].
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