Abstract
Non-melanoma skin cancers (NMSCs) are the leading cause of skin cancer-related morbidity and mortality. Effective strategies are needed to control NMSC occurrence and progression. Non-toxic, plant-derived extracts have been shown to exert multiple anti-cancer effects. Graviola (Annona muricata), a tropical fruit-bearing plant, has been used in traditional medicine against multiple human diseases including cancer. The current study investigated the effects of graviola leaf and stem extract (GLSE) and its solvent-extracted fractions on two human NMSC cell lines, UW-BCC1 and A431. GLSE was found to: (i) dose-dependently suppress UW-BCC1 and A431 cell growth, motility, wound closure, and clonogenicity; (ii) induce G0/G1 cell cycle arrest by downregulating cyclin/cdk factors while upregulating cdk inhibitors, and (iii) induce apoptosis as evidenced by cleavage of caspases-3, -8 and PARP. Further, GLSE suppressed levels of activated hedgehog (Hh) pathway components Smo, Gli 1/2, and Shh while inducing SuFu. GLSE also decreased the expression of pro-apoptotic protein Bax while decreasing the expression of the anti-apoptotic protein Bcl-2. We determined that these activities were concentrated in an acetogenin/alkaloid-rich dichloromethane subfraction of GLSE. Our data identify graviola extracts and their constituents as promising sources for new chemopreventive and therapeutic agent(s) to be further developed for the control of NMSCs.
Highlights
Non-melanoma skin cancer (NMSC), the most prevalent form of cancer worldwide, is classified into two major forms, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma [1]
The present study investigated the effects of a powdered extract of graviola aerial parts, and successively extracted subfractions thereof, on two NMSC cell lines, namely UW-BCC1, derived from a basal cell carcinoma [13], and A431 [33], representing squamous cell carcinoma compared to control keratinocytes
Since different parts of the graviola plant have been reported to possess anti-cancer activities against multiple non-skin cancer cell types, we first investigated the effect of graviola leaf and stem extract (GLSE) on the growth, viability, migration and clonogenic potential of UW-BCC1 and A431 cell lines as compared to control non-cancerous human epidermal keratinocytes (NHEKs)
Summary
Non-melanoma skin cancer (NMSC), the most prevalent form of cancer worldwide, is classified into two major forms, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) [1]. CSCCs are much more dangerous due to their likelihood to invade, bleed and metastasize, and represent a major cause of morbidity and mortality worldwide [10,14,15]. Together, these forms of NMSC present a major public health burden across the world [16]; in the U.S, their incidence has increased over 300% since 1994 [17] with about 5.4 million cases being treated for NMSC yearly [9], making it the fifth highest total for all cancers [18]. Skin carcinogenesis primarily occurs on sun-exposed areas including the face, ears, head, neck, hands, scalp, etc. [13,19], and fair-skinned individuals with history of sun tanning or living near the equator [7,8,13,20,21]
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