TY - JOUR
T1 - Graviola (Annona muricata) exerts anti-proliferative, anti-clonogenic and pro-apoptotic effects in human non-melanoma skin cancer UW-BCC1 and A431 cells in vitro
T2 - Involvement of hedgehog signaling
AU - Chamcheu, Jean Christopher
AU - Rady, Islam
AU - Chamcheu, Roxane Cherille N.
AU - Siddique, Abu Bakar
AU - Bloch, Melissa B.
AU - Mbeumi, Sergette Banang
AU - Babatunde, Abiola S.
AU - Uddin, Mohammad B.
AU - Noubissi, Felicite K.
AU - Jurutka, Peter
AU - Liu, Yong Yu
AU - Spiegelman, Vladimir S.
AU - Whitfield, G. Kerr
AU - El Sayed, Khalid A.
N1 - Funding Information:
This work was supported in part by a startup fund from the University of Louisiana at Monroe (ULM), School of Pharmacy to J.C.C., a ULM College of Pharmacy Faculty Research Seed Grant (#5CALHN-260615) to J.C.C., a Carson Research Scholar Award in Psoriasis from American Skin Association (ASA) to J.C.C., and a UW-Madison Skin Disease Research Center (SDRC) Pilot and Feasibility Research Award from NIH/NIAMS grant P30 AR066524 to J.C.C., a POHOFI Inc. Pre-College Intern Scholarship Award to R.-C.N.C., NIH grant NIH R15CA16747 to K.A.E.S, NIH grant R01CA140285 to P.W.J., and a grant from the University of Arizona, Department of Basic Medical Sciences to GKW.
Funding Information:
Funding:ThisworkwassupportedinpartbyastartupfundfromtheUniversityofLouisianaatMonroe(ULM), School ofPharmacytoJ.C.C.,aULMCollegeofPharmacyFacultyResearchSeedGrant(#5CALHN-260615)to J.C.C., a Carson Research Scholar Award in Psoriasis from American Skin Association (ASA) to J.C.C., and a UW-Madison Skin Disease Research Center (SDRC) Pilot and Feasibility Research Award from NIH/NIAMS grant P30 AR066524 to J.C.C., a POHOFI Inc. Pre-College Intern Scholarship Award to R.-C.N.C., NIH grant NIH R15CA16747 to K.A.E.S, NIH grant R01CA140285 to P.W.J., and a grant from the University of Arizona, DepartmentofBasicMedicalSciencestoGKW.
Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2018/6/16
Y1 - 2018/6/16
N2 - 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.
AB - 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.
KW - Annona muricata
KW - Apoptosis
KW - Basal cell carcinoma
KW - Cutaneous squamous cell carcinoma
KW - Graviola
KW - Hedgehog signaling pathway
KW - Natural products chemistry
KW - Non-melanoma skin cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85048672273&partnerID=8YFLogxK
U2 - 10.3390/ijms19061791
DO - 10.3390/ijms19061791
M3 - Article
C2 - 29914183
AN - SCOPUS:85048672273
SN - 1661-6596
VL - 19
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 6
M1 - 1791
ER -