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: Involvement of Hedgehog Signaling

Jean Christopher Chamcheu, Islam Rady, Roxane-Cherille N Chamcheu, Abu Bakar Siddique, Melissa B Bloch, Sergette Banang Mbeumi, Abiola S Babatunde, Mohammad B Uddin, Felicite K Noubissi, Peter W Jurutka, Yong-Yu Liu, Vladimir S Spiegelman, G Kerr Whitfield, Khalid A El Sayed, Jean Christopher Chamcheu, Islam Rady, Roxane-Cherille N Chamcheu, Abu Bakar Siddique, Melissa B Bloch, Sergette Banang Mbeumi, Abiola S Babatunde, Mohammad B Uddin, Felicite K Noubissi, Peter W Jurutka, Yong-Yu Liu, Vladimir S Spiegelman, G Kerr Whitfield, Khalid A El Sayed

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.

Keywords: Annona muricata; Hedgehog signaling pathway; apoptosis; basal cell carcinoma; cutaneous squamous cell carcinoma; graviola; natural products chemistry; non-melanoma skin cancer.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Graviola aerial parts including leaves, stems and fruits. Effects of GLSE on UW-BCC1 and A431 cell viability after (B) 24 h or (C) 48 h and colony formation of non-melanoma skin cancer (NMSC) cells. Cells were incubated with the indicated concentration of GLSE, and percentage cell viabilities, determined by CCK-8 assay for UW-BCC1 cells, and by MTT assay for A431 and NHEK cells, were plotted against the doses of GLSE (μg/mL). Values used for plotting are means of experiments performed three times, with each concentration tested in 7–8 wells. Effects of GLSE on clonogenicity of UW-BCC1 (D and F) and A431 (E and G) cells as detected by colony formation assay. The purple color shows the density of stained cell colonies in the different treatment groups. Means for each cell line were compared against NHEKs in viability studies. Statistical differences from control cultures are shown as bar graphs with error bars representing the means ± SD in panels (F) and (G); * p < 0.05 and ** p < 0.01 and *** p < 0.001 vs. control (DMSO-treated) cells.
Figure 2
Figure 2
GLSE induces G0/G1 phase cell cycle arrest of non-melanoma skin cancer cells. UW-BCC1 and A431 cells treated with GLSE for 24 h were stained with the Apo-Direct kit following the manufacturer’s protocol and analyzed by flow cytometry. Plots and percentage distribution of cell population in the G0/G1, G2/M and S phases of the cell cycle are shown in the insert in each panel: (A) results from UW-BCC1 cells at different GLSE doses, and (B) results from A431 cells. (B–D) Quantification of effects of GLSE treatment on cell cycle regulatory proteins. Whole cell lysates of UW-BCC1 (bottom left set of images in panels (B)–(D)) and A431 (bottom right set of images) with/without GLSE (0–160 µg/mL: 24 h) were subjected to SDS-polyacrylamide gel electrophoresis. Blots containing resolved proteins from UW-BCC1 and A431 cells were analyzed by immunoblotting with antibodies for CDK2, CDK4, Cyclin D1, Cyclin E1, p21WAF1 or p27kip1. Equal loading was confirmed by re-probing with β-Actin, GAPDH or vinculin as loading controls. The immunoblot images shown are representative of three independent experiments with similar results. Quantification data are shown in the supplementary Figure S4.
Figure 3
Figure 3
GLSE induces apoptosis of UW-BCC1 and A431 cells through activation of caspases 3/8, and PARP, and suppression of Bcl-2. (A) UW-BCC1 and A431 cells treated with or without GLSE (0–120 µg/mL: 24 h) were labeled with the Apo-Direct kit and analyzed by flow cytometry. Percentage of apoptotic cells observed (mean ± SD) with each dose of GLSE are shown in the box inserts in each panel. All experiments were performed in triplicate. (B,C) Whole cell lysates of UW-BCC1 (left panels) and A431 cells (right panels) treated with/without GLSE (0–160 µg/mL, 24 h) were subjected to SDS-polyacrylamide gel electrophoresis and blots were probed with antisera to proteins involved in apoptosis pathways, showing (B) expression levels of caspase-3 and caspase-8 in both the intact and cleaved forms; and (C) expression levels of Bax, Bcl-2 and PARP, the latter in both the 116 kDa and 85 kDa forms. Equal protein loading was confirmed by re-probing with β-Actin or GAPDH. The immunoblots shown are representative of three independent experiments with similar results. Data represent the means of three independent experiments each conducted in triplicates ± SD vs. control (DMSO-treated cells), and bar graphs for (B) and (C) representing the means ± SD are presented in Figure S6.
Figure 4
Figure 4
GLSE modulates Hedgehog Signaling Pathway Components in UW-BCC1 and A431 Cells. Whole cell lysates of (A) UW-BCC1 and (B) A431cells treated with/without GLSE (0–160 µg/mL: 24 h) were subjected to SDS-polyacrylamide gel electrophoresis and blots were probed with antisera to hedgehog pathway proteins Shh, Smo, Gli1, Gli2, and SuFu. Equal loading was confirmed by re-probing with GAPDH, β-Actin, GAPDH and vinculin. The immunoblots shown are representative of three independent experiments, each conducted in duplicate, which all gave similar results. Bars represent the means ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p <0.0001 vs. control (DMSO-treated) cells.
Figure 5
Figure 5
Different solvent-extracted fractions of graviola stem and leaf powder extract display differential inhibition of cell viability in non-melanoma skin cancer (NMSC) cells. UW-BCC1 and A431 as well as control NHEKn cells were treated with one of three fractions of graviola (n-hexane, dichloromethane, or methanol) for 48 h, and cell viability was determined by MTT assay. Bar graphs show the effect (Mean ± SD) of each fraction on the % viability after each treatment, with IC50 values in (A) UW-BCC1, (B) A431 and (C) NHEKn cells, at 48 h, shown above the bars. All experiments were performed in triplicate. Details are described in Methods. The p values vs. control (DMSO-treated) cells: * p < 0.05 and ** p < 0.01 and *** p < 0.001.
Figure 6
Figure 6
Phytochemical fingerprint of MeOH, DCM and Hexane extracts: 1H NMR spectra of graviola extracts in CDCl3 at 400 MHz. (A) Spectrum of the n-hexane subfraction and expansion of its circled downfield segment at upper left of panel; (B) Spectrum of the DCM subfraction and expansion of its circled downfield segment rich in olefinic, aromatic, heteroaromatic, phenolic hydroxy and/or NH groups; and (C) MeOH extract spectrum in CD3OD and expansion of its circled downfield segment rich in aromatic and phenolic hydroxy groups.
Figure 7
Figure 7
Chemical fingerprint of the dichloromethane (DCM) subfraction of GLSE. (A) Full PENDANT-13C NMR spectrum of the graviola DCM extract in CDCl3 showing methylene and quaternary carbons up and methine and methyl carbons down. The full spectrum shows four different signal clusters as explained in the text; and (B) Expansion of the circled portion of the spectrum from panel A containing lactone/ester carbonyl and ketone carbons clusters circled in PENDANT spectrum.
Figure 8
Figure 8
Chemical fingerprint of the graviola DCM extract. Electrospray ionization–mass spectrometry (ESI-MS) analysis of graviola DCM extract in negative ion mode. The cluster at m/z 567.4–685.5 is suggestive of acetogenin ion peaks while the cluster at m/z 239–327 is suggestive of potential alkaloid and smaller acetogenin ion peaks.

References

    1. Fahradyan A., Howell A.C., Wolfswinkel E.M., Tsuha M., Sheth P., Wong A.K. Updates on the Management of Non-Melanoma Skin Cancer (NMSC) Healthcare (Basel) 2017;5:82. doi: 10.3390/healthcare5040082.
    1. Eisemann N., Waldmann A., Geller A.C., Weinstock M.A., Volkmer B., Greinert R., Breitbart E.W., Katalinic A. Non-melanoma skin cancer incidence and impact of skin cancer screening on incidence. J. Investig. Dermatol. 2014;134:43–50. doi: 10.1038/jid.2013.304.
    1. Kim T., Havighurst T., Kim K., Hebbring S.J., Ye Z., Aylward J., Keles S., Xu Y.G., Spiegelman V.S. RNA-Binding Protein IGF2BP1 in Cutaneous Squamous Cell Carcinoma. J. Investig. Dermatol. 2017;137:772–775. doi: 10.1016/j.jid.2016.10.042.
    1. Marzuka A.G., Book S.E. Basal cell carcinoma: Pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. Yale J. Biol. Med. 2015;88:167–179.
    1. Guy G.P., Jr., Machlin S.R., Ekwueme D.U., Yabroff K.R. Prevalence and costs of skin cancer treatment in the U.S., 2002–2006 and 2007–2011. Am. J. Prev. Med. 2015;48:183–187. doi: 10.1016/j.amepre.2014.08.036.
    1. Guy G.P., Jr., Thomas C.C., Thompson T., Watson M., Massetti G.M., Richardson L.C. Vital signs: Melanoma incidence and mortality trends and projections—United States, 1982–2030. MMWR Morb. Mortal. Wkly. Rep. 2015;64:591–596.
    1. Robinson J.K. Sun exposure, sun protection, and vitamin D. JAMA. 2005;294:1541–1543. doi: 10.1001/jama.294.12.1541.
    1. Stern R.S. Prevalence of a history of skin cancer in 2007: Results of an incidence-based model. Arch. Dermatol. 2010;146:279–282. doi: 10.1001/archdermatol.2010.4.
    1. Rogers H.W., Weinstock M.A., Feldman S.R., Coldiron B.M. Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. JAMA Dermatol. 2015;151:1081–1086. doi: 10.1001/jamadermatol.2015.1187.
    1. Van der Geer S., Siemerink M., Reijers H.A., Verhaegh M.E., Ostertag J.U., Neumann H.A., Krekels G.A. The incidence of skin cancer in dermatology. Clin. Exp. Dermatol. 2013;38:724–729. doi: 10.1111/ced.12080.
    1. Tarallo M., Cigna E., Frati R., Delfino S., Innocenzi D., Fama U., Corbianco A., Scuderi N. Metatypical basal cell carcinoma: A clinical review. J. Exp. Clin. Cancer Res. 2008;27:65. doi: 10.1186/1756-9966-27-65.
    1. Athar M., Li C., Kim A.L., Spiegelman V.S., Bickers D.R. Sonic hedgehog signaling in Basal cell nevus syndrome. Cancer Res. 2014;74:4967–4975. doi: 10.1158/0008-5472.CAN-14-1666.
    1. Noubissi F.K., Kim T., Kawahara T.N., Aughenbaugh W.D., Berg E., Longley B.J., Athar M., Spiegelman V.S. Role of CRD-BP in the growth of human basal cell carcinoma cells. J. Investig. Dermatol. 2014;134:1718–1724. doi: 10.1038/jid.2014.17.
    1. Anand P., Kunnumakkara A.B., Sundaram C., Harikumar K.B., Tharakan S.T., Lai O.S., Sung B., Aggarwal B.B. Cancer is a preventable disease that requires major lifestyle changes. Pharm. Res. 2008;25:2097–2116. doi: 10.1007/s11095-008-9661-9.
    1. Stratigos A., Garbe C., Lebbe C., Malvehy J., del Marmol V., Pehamberger H., Peris K., Becker J.C., Zalaudek I., Saiag P., et al. Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur. J. Cancer. 2015;51:1989–2007. doi: 10.1016/j.ejca.2015.06.110.
    1. Lomas A., Leonardi-Bee J., Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br. J. Dermatol. 2012;166:1069–1080. doi: 10.1111/j.1365-2133.2012.10830.x.
    1. Nowotarski S.L., Feith D.J., Shantz L.M. Skin Carcinogenesis Studies Using Mouse Models with Altered Polyamines. Cancer Growth Metastasis. 2015;8:17–27. doi: 10.4137/CGM.S21219.
    1. Cronin K.A., Lake A.J., Scott S., Sherman R.L., Noone A.M., Howlader N., Henley S.J., Anderson R.N., Firth A.U., Ma J., et al. Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics. Cancer. 2018 doi: 10.1002/cncr.31551.
    1. Pleasance E.D., Cheetham R.K., Stephens P.J., McBride D.J., Humphray S.J., Greenman C.D., Varela I., Lin M.L., Ordonez G.R., Bignell G.R., et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;463:191–196. doi: 10.1038/nature08658.
    1. Rippey J.J. Why classify basal cell carcinomas? Histopathology. 1998;32:393–398. doi: 10.1046/j.1365-2559.1998.00431.x.
    1. Xiang F., Lucas R., Hales S., Neale R. Incidence of nonmelanoma skin cancer in relation to ambient UV radiation in white populations, 1978–2012: Empirical relationships. JAMA Dermatol. 2014;150:1063–1071. doi: 10.1001/jamadermatol.2014.762.
    1. Ananthaswamy H.N., Pierceall W.E. Molecular mechanisms of ultraviolet radiation carcinogenesis. Photochem. Photobiol. 1990;52:1119–1136. doi: 10.1111/j.1751-1097.1990.tb08452.x.
    1. Gupta S., Takebe N., Lorusso P. Targeting the Hedgehog pathway in cancer. Ther. Adv. Med. Oncol. 2010;2:237–250. doi: 10.1177/1758834010366430.
    1. Bale A.E., Yu K.P. The hedgehog pathway and basal cell carcinomas. Hum. Mol. Genet. 2001;10:757–762. doi: 10.1093/hmg/10.7.757.
    1. Ciani F., Tafuri S., Troiano A., Cimmino A., Fioretto B.S., Guarino A.M., Pollice A., Vivo M., Evidente A., Carotenuto D., et al. Anti-proliferative and pro-apoptotic effects of Uncaria tomentosa aqueous extract in squamous carcinoma cells. J. Ethnopharmacol. 2018;211:285–294. doi: 10.1016/j.jep.2017.09.031.
    1. Newman D.J., Cragg G.M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016;79:629–661. doi: 10.1021/acs.jnatprod.5b01055.
    1. Schmidt B., Ribnicky D.M., Poulev A., Logendra S., Cefalu W.T., Raskin I. A natural history of botanical therapeutics. Metabolism. 2008;57:39. doi: 10.1016/j.metabol.2008.03.001.
    1. Gavamukulya Y., Wamunyokoli F., El-Shemy H.A. Annona muricata: Is the natural therapy to most disease conditions including cancer growing in our backyard? A systematic review of its research history and future prospects. Asian Pac. J. Trop. Med. 2017;10:835–848. doi: 10.1016/j.apjtm.2017.08.009.
    1. Moghadamtousi S.Z., Fadaeinasab M., Nikzad S., Mohan G., Ali H.M., Kadir H.A. Annona muricata (Annonaceae): A Review of Its Traditional Uses, Isolated Acetogenins and Biological Activities. Int. J. Mol. Sci. 2015;16:15625–15658. doi: 10.3390/ijms160715625.
    1. Coria-Tellez A.V., Montalvo-Gonzalez E., Yahia E.M., Obledo-Vazquez E.N. Annona muricata: A comprehensive review on its traditional medicinal uses, phytochemicals, pharmacological activities, mechanisms of action and toxicity. Arab. J. Chem. 2017;30 doi: 10.1016/j.arabjc.2016.01.004.
    1. Torres M.P., Rachagani S., Purohit V., Pandey P., Joshi S., Moore E.D., Johansson S.L., Singh P.K., Ganti A.K., Batra S.K. Graviola: A novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism. Cancer Lett. 2012;323:29–40. doi: 10.1016/j.canlet.2012.03.031.
    1. Prabhakaran K., Ramasamy G., Doraisamy U., Mannu J.K.R., Murugesan J.R. Polyketide Natural Products, Acetogenins from Graviola (Annona muricata L), its Biochemical, Cytotoxic Activity and Various Analyses Through Computational and Bio-Programming Methods. Curr. Pharm. Des. 2016;22:5204–5210. doi: 10.2174/1381612822666160531163144.
    1. Giard D.J., Aaronson S.A., Todaro G.J., Arnstein P., Kersey J.H., Dosik H., Parks W.P. In vitro cultivation of human tumors: Establishment of cell lines derived from a series of solid tumors. J. Natl. Cancer Inst. 1973;51:1417–1423. doi: 10.1093/jnci/51.5.1417.
    1. Chen A., Huang X., Xue Z., Cao D., Huang K., Chen J., Pan Y., Gao Y. The Role of p21 in Apoptosis, Proliferation, Cell Cycle Arrest, and Antioxidant Activity in UVB-Irradiated Human HaCaT Keratinocytes. Med. Sci. Monit. Basic Res. 2015;21:86–95.
    1. Soldani C., Scovassi A.I. Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: An update. Apoptosis Int. J. Progr. Cell Death. 2002;7:321–328. doi: 10.1023/A:1016119328968.
    1. Ebrahim H.Y., Akl M.R., Elsayed H.E., Hill R.A., El Sayed K.A. Usnic Acid Benzylidene Analogues as Potent Mechanistic Target of Rapamycin Inhibitors for the Control of Breast Malignancies. J. Nat. Prod. 2017;80:932–952. doi: 10.1021/acs.jnatprod.6b00917.
    1. Ebrahim H.Y., Mohyeldin M.M., Hailat M.M., El Sayed K.A. (1S,2E,4S,7E,11E)-2,7,11-Cembratriene-4,6-diol semisynthetic analogs as novel c-Met inhibitors for the control of c-Met-dependent breast malignancies. Bioorg. Med. Chem. 2016;24:5748–5761. doi: 10.1016/j.bmc.2016.09.032.
    1. Elsayed H.E., Ebrahim H.Y., Haggag E.G., Kamal A.M., El Sayed K.A. Rationally designed hecogenin thiosemicarbazone analogs as novel MEK inhibitors for the control of breast malignancies. Bioorg. Med. Chem. 2017;25:6297–6312. doi: 10.1016/j.bmc.2017.09.033.
    1. Rady I., Bloch M.B., Chamcheu R.-C.N., Banang-Mbeumi S., Anwar M.R., Mohamed H., Babatunde A.S., Kuiate J.R., Noubissi F.K., El Sayed K.A., et al. Anti-cancer Properties of Graviola (Annona muricata): A Comprehensive Mechanistic Review. Oxidative Medicine and Cellular Longevity. 2018 In press.
    1. Ekstrom A.M., Serafini M., Nyren O., Hansson L.E., Ye W., Wolk A. Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: A population-based case-control study in Sweden. Int. J. Cancer. 2000;87:133–140. doi: 10.1002/1097-0215(20000701)87:1<133::AID-IJC20>;2-E.
    1. Guo W.D., Hsing A.W., Li J.Y., Chen J.S., Chow W.H., Blot W.J. Correlation of cervical cancer mortality with reproductive and dietary factors, and serum markers in China. Int. J. Epidemiol. 1994;23:1127–1132. doi: 10.1093/ije/23.6.1127.
    1. Kellen E., Zeegers M., Paulussen A., Van Dongen M., Buntinx F. Fruit consumption reduces the effect of smoking on bladder cancer risk. The Belgian case control study on bladder cancer. Int. J. Cancer. 2006;118:2572–2578. doi: 10.1002/ijc.21714.
    1. Liu R.H. Dietary bioactive compounds and their health implications. J. Food Sci. 2013;78(Suppl. 1):A18–A25. doi: 10.1111/1750-3841.12101.
    1. Syed D.N., Mukhtar H. Botanicals for the prevention and treatment of cutaneous melanoma. Pigment Cell. Melanoma Res. 2011;24:688–702. doi: 10.1111/j.1755-148X.2011.00851.x.
    1. Syed D.N., Chamcheu J.C., Adhami V.M., Mukhtar H. Pomegranate extracts and cancer prevention: Molecular and cellular activities. Anti-Cancer Agents Med. Chem. 2013;13:1149–1161. doi: 10.2174/1871520611313080003.
    1. Kim J. Protective effects of Asian dietary items on cancers—Soy and ginseng. Asian Pac. J. Cancer Prev. 2008;9:543–548.
    1. Lansky E.P., Jiang W., Mo H., Bravo L., Froom P., Yu W., Harris N.M., Neeman I., Campbell M.J. Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Investig. New Drugs. 2005;23:11–20. doi: 10.1023/B:DRUG.0000047101.02178.07.
    1. Seeram N.P., Adams L.S., Hardy M.L., Heber D. Total cranberry extract versus its phytochemical constituents: Antiproliferative and synergistic effects against human tumor cell lines. J. Agric. Food Chem. 2004;52:2512–2517. doi: 10.1021/jf0352778.
    1. Viladomiu M., Hontecillas R., Lu P., Bassaganya-Riera J. Preventive and prophylactic mechanisms of action of pomegranate bioactive constituents. Evid.-Based Complement. Alternat. Med. 2013;2013:789764. doi: 10.1155/2013/789764.
    1. Baillon L., Basler K. Reflections on cell competition. Semin. Cell Dev. Biol. 2014;32:137–144. doi: 10.1016/j.semcdb.2014.04.034.
    1. Sanchez I., Dynlacht B.D. New insights into cyclins, CDKs, and cell cycle control. Semin. Cell Dev. Biol. 2005;16:311–321. doi: 10.1016/j.semcdb.2005.02.007.
    1. Santamaria D., Ortega S. Cyclins and CDKS in development and cancer: Lessons from genetically modified mice. Front. Biosci. 2006;11:1164–1188. doi: 10.2741/1871.
    1. Sola S., Morgado A.L., Rodrigues C.M. Death receptors and mitochondria: Two prime triggers of neural apoptosis and differentiation. Biochim. Biophys. Acta. 2013;1830:2160–2166. doi: 10.1016/j.bbagen.2012.09.021.
    1. Cerqueira A., Martin A., Symonds C.E., Odajima J., Dubus P., Barbacid M., Santamaria D. Genetic characterization of the role of the Cip/Kip family of proteins as cyclin-dependent kinase inhibitors and assembly factors. Mol. Cell. Biol. 2014;34:1452–1459. doi: 10.1128/MCB.01163-13.
    1. Kasibhatla S., Tseng B. Why target apoptosis in cancer treatment? Mol. Cancer Ther. 2003;2:573–580.
    1. Khan K.H., Blanco-Codesido M., Molife L.R. Cancer therapeutics: Targeting the apoptotic pathway. Crit. Rev. Oncol. Hematol. 2014;90:200–219. doi: 10.1016/j.critrevonc.2013.12.012.
    1. Asare G.A., Afriyie D., Ngala R.A., Abutiate H., Doku D., Mahmood S.A., Rahman H. Antiproliferative activity of aqueous leaf extract of Annona muricata L. on the prostate, BPH-1 cells, and some target genes. Integr. Cancer Ther. 2015;14:65–74. doi: 10.1177/1534735414550198.
    1. Zorofchian Moghadamtousi S., Karimian H., Rouhollahi E., Paydar M., Fadaeinasab M., Abdul Kadir H. Annona muricata leaves induce G(1) cell cycle arrest and apoptosis through mitochondria-mediated pathway in human HCT-116 and HT-29 colon cancer cells. J. Ethnopharmacol. 2014;156:277–289. doi: 10.1016/j.jep.2014.08.011.
    1. Syed Najmuddin S.U., Romli M.F., Hamid M., Alitheen N.B., Nik Abd Rahman N.M. Anti-cancer effect of Annona Muricata Linn Leaves Crude Extract (AMCE) on breast cancer cell line. BMC Complement. Altern. Med. 2016;16:311. doi: 10.1186/s12906-016-1290-y.
    1. Pieme C.A., Kumar S.G., Dongmo M.S., Moukette B.M., Boyoum F.F., Ngogang J.Y., Saxena A.K. Antiproliferative activity and induction of apoptosis by Annona muricata (Annonaceae) extract on human cancer cells. BMC Complement. Altern. Med. 2014;14:516. doi: 10.1186/1472-6882-14-516.
    1. Wang X.D., Inzunza H., Chang H., Qi Z., Hu B., Malone D., Cogswell J. Mutations in the hedgehog pathway genes SMO and PTCH1 in human gastric tumors. PLoS ONE. 2013;8:e54415. doi: 10.1371/journal.pone.0054415.
    1. Jain S., Song R., Xie J. Sonidegib: Mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas. Onco Targets Ther. 2017;10:1645–1653. doi: 10.2147/OTT.S130910.
    1. Basset-Seguin N., Hauschild A., Grob J.J., Kunstfeld R., Dreno B., Mortier L., Ascierto P.A., Licitra L., Dutriaux C., Thomas L., et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): A pre-planned interim analysis of an international, open-label trial. Lancet Oncol. 2015;16:729–736. doi: 10.1016/S1470-2045(15)70198-1.
    1. Sekulic A., Migden M.R., Oro A.E., Dirix L., Lewis K.D., Hainsworth J.D., Solomon J.A., Yoo S., Arron S.T., Friedlander P.A., et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med. 2012;366:2171–2179. doi: 10.1056/NEJMoa1113713.
    1. Fecher L.A., Sharfman W.H. Advanced basal cell carcinoma, the hedgehog pathway, and treatment options—Role of smoothened inhibitors. Biologics. 2015;9:129–140. doi: 10.2147/BTT.S54179.
    1. Lacouture M.E., Dreno B., Ascierto P.A., Dummer R., Basset-Seguin N., Fife K., Ernst S., Licitra L., Neves R.I., Peris K., et al. Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma. Oncologist. 2016;21:1218–1229. doi: 10.1634/theoncologist.2016-0186.
    1. Kainu K., Kivinen K., Zucchelli M., Suomela S., Kere J., Inerot A., Baker B.S., Powles A.V., Fry L., Samuelsson L., et al. Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families. Exp. Dermatol. 2009;18:109–115. doi: 10.1111/j.1600-0625.2008.00769.x.
    1. Bhutani T., Abrouk M., Sima C.S., Sadetsky N., Hou J., Caro I., Chren M.M., Arron S.T. Risk of cutaneous squamous cell carcinoma after treatment of basal cell carcinoma with vismodegib. J. Am. Acad. Dermatol. 2017;77:713–718. doi: 10.1016/j.jaad.2017.03.038.
    1. Deep G., Kumar R., Jain A.K., Dhar D., Panigrahi G.K., Hussain A., Agarwal C., El-Elimat T., Sica V.P., Oberlies N.H., et al. Graviola inhibits hypoxia-induced NADPH oxidase activity in prostate cancer cells reducing their proliferation and clonogenicity. Sci. Rep. 2016;6:23135. doi: 10.1038/srep23135.
    1. Dai Y., Hogan S., Schmelz E.M., Ju Y.H., Canning C., Zhou K. Selective growth inhibition of human breast cancer cells by graviola fruit extract in vitro and in vivo involving downregulation of EGFR expression. Nutr. Cancer. 2011;63:795–801. doi: 10.1080/01635581.2011.563027.
    1. Chamcheu J.C., Afaq F., Syed D.N., Siddiqui I.A., Adhami V.M., Khan N., Singh S., Boylan B.T., Wood G.S., Mukhtar H. Delphinidin, a dietary antioxidant, induces human epidermal keratinocyte differentiation but not apoptosis: Studies in submerged and three-dimensional epidermal equivalent models. Exp. Dermatol. 2013;22:342–348. doi: 10.1111/exd.12140.
    1. Chamcheu J.C., Lorie E.P., Akgul B., Bannbers E., Virtanen M., Gammon L., Moustakas A., Navsaria H., Vahlquist A., Torma H. Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines: Trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress condition. J. Dermatol. Sci. 2009;53:198–206. doi: 10.1016/j.jdermsci.2008.11.003.
    1. Chamcheu J.C., Adhami V.M., Esnault S., Sechi M., Siddiqui I.A., Satyshur K.A., Syed D.N., Dodwad S.M., Chaves-Rodriquez M.I., Longley B.J., et al. Dual Inhibition of PI3K/Akt and mTOR by the Dietary Antioxidant, Delphinidin, Ameliorates Psoriatic Features In Vitro and in an Imiquimod-Induced Psoriasis-Like Disease in Mice. Antioxid. Redox Signal. 2017;26:49–69. doi: 10.1089/ars.2016.6769.

Source: PubMed

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