1. Natural Extracts against Cancer

Natural Plant extracts have been used for centuries by many cultures and civilizations as a basis for treating various diseases. More than 80% of the global population now depends on natural plant extracts through traditional therapies. ^{[1, 2, 3]} Recent investigators have focused on the progression, treatment and prevention of cancer with such compounds but room for improvement still remains.

To date, the use of conventional synthetic chemotherapeutic drugs lack the properties to be considered as effective therapeutic agents, with most of those associated with severe side effects and toxicity of the normal host cells. Whereas an alternative therapeutic approach that uses natural plant extracts is advantageous vs conventional therapy with limited side effects.

One of the first systematic approaches was carried out in 1950 with the vinca alkaloids (vinblastin and vincristine) discovery, isolated from the Catharanthus roseus G. Don. (Apocynaceae) followed by a number of effective extracts such as Triptolide (Tripterigium wilfordii), Amygdalin (B12), Achyranthes aspera Linn. (Family-Amaranthaceae) etc ^{[4, 5, 6]}.

2. Graviola History

Graviola belongs to Annonaceae family, Annona genus and muricata species. Graviola is a fruit tree with many uses in traditional and alternative medicine. Graviola, soursop, guanábana, guanábano, guanavana, guanaba, corossol épineux, huanaba, toge-banreisi, durian benggala, nangka blanda, cachiman épineux are altering names for this evergreen plant that is mostly distributed in tropical and subtropical regions of the world. Graviola is a heart shaped edible fruit and together with its leaves, root and seeds is known to have beneficial properties in alternative medicine ^[7].

The fruits of Graviola are extensively used to make candies, syrups, ice creams, shakes and beverages. A wide range of ethno-medicinal activities in Africa and South America extensively use this plant in their conventional medicine. A number of laboratories have reported Graviola’s for its benifical actions against anticonvulsant, antiparasitic, anti-arthritic, antimalarial, antidiabetic hepatoprotective and andicancer activities. Biological and chemical characterization studies indicate that annonaceous acetogenins are the main ingredients of Graviola ^{[8, 9, 10]}.

Nowadays more than 100 annonaceous acetogenins that are generally characterized as a family of natural products with antitumor activities, from roots, leaves, barks, fruits and seeds of Graviola have been widely used in alternative medicine for many purposes. In the Peruvian Andes for example, the Graviola leaves are used to combat parasites and treat diabetes. In the Brazilian Amazon the leaves were used to treat liver problems and the leave – extracted oil is believed to help with rheumatism, neuralgia and arthritis. In the Eastern Andes and Jamaica, Haiti the juice of Graviola was used to stop diarrhea, used as muscle relaxant and lower the intestinal acidity [11-15]^[11].

Other reports have demonstrated that Graviola has a number of biological activities such as antifungal, anti-bacterial, anti-malarial and antioxidant. Furthermore, it has been showed to have anti-cancer properties on multi-drug resistant cancer cell lines. ^{[16, 17, 18, 19, 20]} The ability of Graviola to have selective growth inhibition against a variety of cancer cells including lung carcinoma cell lines, breast solid tumor lines, prostate adenocarcinoma, pancreatic carcinoma cell lines, colon adenocarcinoma cell lines, liver cancer cell lines, human lymphoma cell lines, and multi-drug resistant human breast adenocarcinoma will be discussed based on previously published data ^{[21, 22, 23, 24, 25, 26]}.

Graviolas fruit flesh consists of 80% water, 1% protein, 18% carbohydrates and small amount of vitamins B, B2, C, potassium and dietary fiber. ^{[27, 28]} The main group, annonaceous acetogenin, is a unique set of derivatives of C35 or C37 long chain fatty acids derived from the polyketide pathway (Figure 1). The annonaceous acetogenins found in Graviola include Annocatalin, annohexocin, annomonicin, annomontacin, annomuricatin A & B, annomuricin A thruE, annomutacin, annonacin, annonacinone, annopentocin A thru C, cis-annonacin, cis-corossolone,cohibin A thru D, corepoxylone, coronin, corossolin, corossolone, donhexocin, epomuricenin A & B,gigantetrocin, gigantetrocin A & B, gigantetrocinone, gigantetronenin, goniothalamicin, iso-annonacin, javoricin, montanacin, montecristin, muracin A thru G, muricapentocin, muricatalicin,muricatalin, muri-catenol, uricatetrocin A & B muricatin D, muricatocin A thru C muricin H,muricin I, muricoreacin, murihexocin 3, murihexocin A thru C, murihexol, murisolin, robustocin, rolliniastatin 1 & 2, saba-delin, solamin, uvariamicin I & IV, xylomaticin isolated from the leaves, root and stem barks of Graviola ^{[29, 30, 31]}.

Download as

• PPT
  PowerPoint Slide
• PNG
  Larger image(png format)

Veiw figureFigures index

•  NEW
  View larger figure in new window

Figure 1.Bullatacin chemical structure, one out of the three main annonaceous acetogenin molecules including asimicin and bullatalicin that it is believed to be the one most bio-active anti-cancer molecule found in the Graviola extract

The essential oil of the fresh fruit pulp contains 2-hexenoic acid methyl ester (23.9%), 2-hexenoic acid ethyl ester (8.6%), 2-octenoic acid methyl ester (5.4%), 2-butenoic acid methyl ester (2.4%), β-caryophyllene (12.7%), 1,8- cineole (9.9%), linalool (7.8%), α-terpineol (2.8%), lialyl propionate (2.2%) and calarence (2.2%) ^[32].

Limited number of published data are found in literature for the anti-carcinogenic potential of Graviola natural extracts. Recent studies have suggested that Graviola also expresses analgestic and anti-inflammatory effects, promotes apoptosis (programmed cell death) and cytotoxicity on cancer cells that may result from the presence of alkaloids, essential oils and acetogenins. ^{[11, 33, 34, 35]} These acetogenins demonstrated to be selective and toxic against various types of cancer cells without harming normal and healthy host cells ^{[36, 37, 38]}.

It has been previously reported that the Graviola extracts have significant anti-cancer effects in a number of cancer cell lines both in vitro and in vivo. ^[39] Studies revealed the Graviola extracts as having selective inhibition of breast cancer cells via EGFR downregulation. The epidermal growth factor receptor (EGFR) is an oncogene frequently overexpressed in breast cancer (BC), and its overexpression has been associated with poor prognosis and drug resistance. EGFR is therefore a rational target for BC therapy development. In addition, experiments showed that Graviola fruit extract (GFE) inhibit the growth of BC cells using xenografts mouse model studies. Moreover, GFE selectively inhibited the growth of EGFR-overexpressing human BC (MDA-MB-468) cells but not in non-tumorigenic human breast epithelial cells (MCF-10A). ^[39] These studies strengthen the evidence that Graviola has selective anti-growth effects between cancer and non-cancer cells.

Another study on breast cancer cells supported that Graviola promotes apoptosis in ER-related pathways. Moreover, Graviola decreased MCF-7 tumor growth while inhibiting ER-cyclin D1 and Bcl-2 protein expressions in nude mice. ^[40] In colon cancer cells, Graviola leaves also has significant effects on cell survival potential via mitochondrial-mediated apoptosis associated with the G1 cell cycle arrest. Graviola induces apoptosis by generating reactive oxygen species ROS and down-regulating the anti-apoptotic Bcl-2 protein, while up-regulating pro-apoptotic Bax protein. These processes subsequently lead to attenuation of mitochondrial membrane potential (MMP) and cytochrome c release. Release of cytochrome c activates apotosome and the intrinsic caspase cascade that triggers execution of apoptosis through DNA fragmentation. ^[41] Graviola has also been reported to have anti-proliferative effects of HL-60 cells via loss of cell viability, loss of MMP, G0/G1 phase cell arrest and morphological apoptotic changes. These results substantiate and confirm that Graviola does indeed have anti-proliferative and cytostatic activity in HL-60 cells ^[42].

In Vitro and in vivo model studies demonstrated the effect of Graviola extract in prostate cancer cell lines. These experiments showed that Graviola promotes necrosis in PC-3 cells through inhibition of tumor mobility and cellular metabolism. Further studies demonstrated downregulation of the expression of the hypoxia-related factors and glycolytic factors following treatment in PC cells with Graviola (i.e. HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) ^[26].

Follow up studies reported the in vivo Graviola leaf extract (GLE) pharmacokinetics and in vitro absorption kinetics resulting in inhibiting in vitro prostate cancer proliferation, viability and clonogenic colonies. Oral administration of 100mg/kg bw GLE showed tumor growth-inhibition in human prostate tumor in xenografts studies. This study also demonstrated the synergy among the constituents of Graviola leaf extract (GLE) compared to its flavonoid-enriched (FEF) and acetogenin-enriched (AEF) fractions ^{[43, 54]}.

In another study Graviola also had effects on Lewis lung carcinoma (LLC) tumor cell lines that were examined both in vivo as well as in vitro. The study suggested that Graviola once again had antitumor activity by inhibiting the normal growth of the lung tumors. ^[47] Further studies also indicated the anti-cancerous and cytotoxic mechanisms of action of Graviola that affected NADH oxidase inhibition in cancer cell lines, downregulation of the P-glycoprotein pump via ATP depletion and Cell cycle arrest at S-phase progression ^{[48, 49, 50, 51]}.

A recently published study demonstrated also the preventive measure against 7,12-dimethylbenzeneanthracene DMBA-induced breast cell proliferation in the breast tissues of female albino mice. Once again, the study supported that the Graviola leaf extract could act as a cancer prevention agent ^[52].

3. Concluding Remarks

Overall, this mini review lists the existing knowledge about the natural plant extract agent, Graviola, and gives an insight on the important in vitro and in vivo studies that have been carried out based on its efficacy and functional characteristics. However, further studies are required to verify the exact properties and the mechanisms of action. Even though several reports demonstrated positive actions of Graviola, more robust and systematic clinical trials to test and verify its true validity and safety are necessary, in order to be confirmed as a therapeutic anti-cancer agent. Thus, well-designed, randomized, double blind trials are of major importance.

Concluding, the present review demonstrates the advantages of the possible use of Graviola for cancer treatment. Existing conventional cancer therapies are known to be highly toxic with severe side-effects that affect the quality of life of the patients and with no more than 6 months contribution of life expectancy ^{[56, 57]}. Therefore, new drugs need to be developed that include bioactive natural molecules such as Graviola that do not have toxic side-effects and are selective in killing cancer cells but not the normal/physiological healthy host cells. Furthermore, pro-inflammatory responses and pathways are activated and suggested to play an important, primary role in tumourgenesis. Graviola with known strong anti-inflammatory effects can warrant a new in vivo study to determine whether one mechanism of action, could possibly be, through specifically inhibiting the site of inflammation in solid cancers ^{[53, 55]}.

Table 1. Scientific findings of previously published work on Graviola

Download as

PowerPoint Slide

Larger image(png format)

• Tables index

Veiw figure

View current table in a new window

References

[1]	Ignacimuthu S, Ayyanar M, Sivaraman S.K., Ethnobotanical investigations among tribes in Madurai district of Tamil Nadu (India). Journal of Ethnobiology and Ethnomedicine, 2. 1. 2006.
	In article		View Article  PubMed
[2]	Elujoba A. A., Odeleye O. M., Ogunyemi C. M., Traditional medicine development for medical and dental primary health care delivery system in Africa. African Journal of Traditional, Complementary and Alternative Medicines, 2. 46. 2005.
	In article
[3]	Tomlinson T. R., Akerele O. Medicinal plants: their role in health and biodiversity. University of Pennsylvania Press, Philadelphia, 1998.
	In article
[4]	Gordon M. C., David J., Plants as a source of anti-cancer agents. Journal of Ethnopharmacology, 100. 72. 2005.
	In article		View Article  PubMed
[5]	Gueritte F., Fahy J., The vinca alkaloids. In Anticancer Agents from Natural Products, edited by Cragg GM, Kingston DGI, Newman DJ. Brunner-Routledge Psychology Press, Taylor & Francis Group, Boca Raton, Chapter 7. 23. 2005.
	In article		View Article
[6]	Patrikios Ioannis, Stephanou Anastasis, Yiallouris Andreas. Tripterygium Wilfordii Extract (Triptolide) and Amygdalin Promotes Cell death in Cancer Cells: True or a Myth. American Journal of Cancer Prevention Vol. 3, No. 4, 2015, pp 77-83.
	In article		View Article
[7]	Mishra, S.; Ahmad, S.; Kumar, N.; Sharma, B.K. Annona muricata(the cancer killer): A review. Glob. J. Pharm. Res. 2013, 2, 1613-1618.
	In article
[8]	Leboeuf, M.; Cavé, A.; Bhaumik, P.; Mukherjee, B.; Mukherjee, R. The phytochemistry of the annonaceae. Phytochemistry1980, 21, 2783-2813.
	In article		View Article
[9]	Adewole, S.O.; Caxton-Martins, E.A. Morphological changes and hypoglycemic effects of Annona muricataLinn. (Annonaceae) leaf aqueous extract on pancreatic B-cells of streptozotocin-treated diabetic rats. Afr. J. Biomed. Res. 2006, 9, 173-187.
	In article
[10]	De Souza, R.; Benassi, E.; da Silva, R.R.; Afonso, S.; Scarminio, I.S. Enhanced extraction yields and mobile phase separations by solvent mixtures for the analysis of metabolites in Annona muricata L. Leaves. J. Sep. Sci. 2009, 32, 4176-4185.
	In article		View Article  PubMed
[11]	De Sousa, O.V.; Vieira, G.D.-V.; de Pinho, J.D.J.R.; Yamamoto, C.H.; Alves, M.S. Antinociceptive and anti-inflammatory activities of the ethanol extract of Annona muricataL.leaves in animal models. Int. J. Mol. Sci. 2010, 11, 2067-2078.
	In article		View Article  PubMed
[12]	Adewole, S.; Ojewole, J. Protective effects of Annona muricatalinn.(annonaceae) leaf aqueous extract on serum lipid profiles and oxidative stress in hepatocytes of streptozotocin-treated diabetic rats. Afr. J. Tradit. Complement. Altern. Med. 2009, 6, 30-41.
	In article
[13]	Watt, J.M.; Breyer-Bnodwijk, M. The Medicinal and Poisonous Plants of Southern and Eastern Africa: Being an Account of Their Medicinal and Other Uses, Chemical Composition, Pharmacological Effects AodToricotogy in Man and Annimal; Lívingstone Ltd.: Edinburgh, UK; London, UK, 1962.
	In article		PubMed
[14]	Jaramillo-Flores, M.; Hernandez-Sanchez, H. Thermal diffusivity of soursop (Annona muricata L.) pulp. J. Food Eng. 2000, 46, 139-143.
	In article		View Article
[15]	Wu, F.-E.; Gu, Z.-M.; Zeng, L.; Zhao, G.-X.; Zhang, Y.; McLaughlin, J.L. Sastrodihardjo, S. Two new cytotoxic monotetrahydrofuran annonaceous acetogenins, annomuricinsa and b, from the leaves of Annona muricata. J. Nat. Prod. 1995, 58, 830-836.
	In article		View Article  PubMed
[16]	Vieira GHF, Mourão JA, Ângelo ÂM, Costa RA, Vieira SDF: Antibacterial effect (in vitro) of Moringaoleifera and Annona muricata against gram positive and gram negative bacteria. Rev Inst Med Trop Sao Paulo 2010, 52(3):129-132.
	In article		View Article  PubMed
[17]	Heinrich M, Kuhnt M, Wright CW, Rimpler H, Phillipson JD, Schandelmaier A, Warhurst DC: Parasitological and microbiological evaluation of mixe Indian medicinal plants (Mexico). J Ethnopharmacol 1992, 36:81-85.
	In article		View Article
[18]	Antoun MD, Gerena L, Milhus WK: Screening of the flora of Puerto rico for potential antimalarial bioactives. Int J Pharmacol 1993, 31:255-258.
	In article		View Article
[19]	Baskar R, Rajeswari V, Kumar TS: In vitro antioxidant studies in leaves of annona species. Indian J ExpBiol 2007, 4:480-485.
	In article
[20]	Luna Jde S, De Carvalho JM, De Lima MR, Bieber LW, Bento Ede S, Franck X, Sant'ana AE: Acetogenins in Annona muricata L. (annonaceae) leaves are potent molluscicides. Nat Prod Res 2006, 20:253-257.
	In article		View Article  PubMed
[21]	Rieser, M. J.; Gu, Z. M.; Fang, X. P.; Zeng, L.; Wood, K. V.; McLaughlin, J. L. Five novel mono-tetrahydrofuran ring acetogenins from the seeds of Annona muricata. J Nat. Prod. 1996, 59, 100.
	In article		View Article  PubMed
[22]	Kim, G. S.; Zeng, L.; Alali, F.; Rogers, L. L.; Wu, F. E.; Sastrodihardjo, S.; McLaughlin, Muricoreacin and murihexocin C, mono-tetrahydrofuran acetogenins, from the leaves of Annona muricataJ. L. Phytochem. 1998, 49, 565.
	In article		View Article
[23]	Chang, F. R.; Wu, Y. C. Novel cytotoxic annonaceous acetogenins from Annona muricata.J Nat. Prod. 2001, 64, 925.
	In article		View Article  PubMed
[24]	Liaw, C. C.; Chang, F. R.; Lin, C. Y.; Chou, C. J.; Chiu, H. F.; Wu, M. J.; Wu, Y. C. J New cytotoxic monotetrahydrofuran annonaceous acetogenins from Annona muricata. Nat. Prod. 2002, 65, 470.
	In article		View Article
[25]	Chang, F. R.; Liaw, C. C.; Lin, C. Y.; Chou, C. J.; Chiu, H. F.; Wu, Y. C. New adjacent Bis-tetrahydrofuran Annonaceous acetogenins from Annona muricata.Planta Medica2003, 69, 241.
	In article		View Article  PubMed
[26]	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.
	In article		View Article  PubMed
[27]	Hann J: A history of the Tumucua Indians and mission. Florida: University Press; 1996:13-21.
	In article
[28]	Pier O: Pacific island ecosystem at risk, “Result set for: Annonaceace Annona muricata”. United States Geological Survey and United States Forest Service: Pier species lists; 2008:8.
	In article
[29]	Rieser MJ, Kozlowski JF, Wood KV, McLaughlin J: Muricatacin: a simple biologically active acetogenin derivative from the seeds of Annona muricata (Annonaceae). Tetrahedron Lett 1991, 32:1137-1140.
	In article		View Article
[30]	CosmeKossouoh , Mansour Moudachirou , Victor Adjakidje , Jean-Claude Chalchat c& Gilles Figuérédo. Essential Oil Chemical Composition of Annona muricata L. Leaves fromBenin, Journal of Essential Oil Research(2007),19:4, 307-309,
	In article
[31]	Badrie N. and Schauss A.G. Soursop (Annona muricata L.): Composition, Nutritional Value, Medicinal Uses, and Toxicology, Bioactive Foods in Promoting Health, 2010, Ch. 39: 621-641
	In article		View Article
[32]	Sulaiman H, Roslida AH, Fezah O, Tan KL, Tor YS, Tan CI: Chemopreventive potential of Annona Muricata L Leaves on chemically-Induced skin papillomagenesis in mice. Asian Pac J Cancer Prev 2012, 13:2532-2533.
	In article
[33]	Leboeuf M, Cavé A, Bhaumik PK, Mukherjee B, Mukherjee R: The phytochemistry of the annonaceae. Phytochem 1982, 21:2783-2813.
	In article		View Article
[34]	Kossouoh C, Moudachirou M, Adjakidje V, Chalchat JC, Figuérédo G: Essential oil chemical composition of Annona muricata L. leaves from Benin. J Ess Oil Res 2007, 19:307-309.
	In article		View Article
[35]	Chang FR, Liaw CC, Lin CY, Chou CJ, Chiu HF, Wu YC: New adjacent bis-tetrahydrofuran annonaceous acetogenins from Annona muricata. Planta Med 2003, 69:241-246.
	In article		View Article  PubMed
[36]	Ekaprasasti NR, Tuti SS, Retno WA: The breast of anticancer from leaf extract of Annona muricata againts cell line in t47d. Int J Applied SciTechnol 2012, 2(1):157-164.
	In article
[37]	Gajalakshmi S, Vijayalakshmi S, Devi. Rajeswari V:Phytochemical and pharmacological properties of Annona muricata: a review. Int J Pharm PharmSci 2012, 4(2):3-6.
	In article
[38]	Ragasa CY, Soriano G, Torres OB, Don MJ, Shen CC: Acetogenins from Annona muricata. Phcog J 2012, 32(4):32-37.
	In article		View Article
[39]	Dai Y, Hogan S, Schmelz EM, Ju YH, 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. [PubMed: 21767082].
	In article		View Article  PubMed
[40]	Yu-Min Koa, Tung-Ying Wub, Yang-Chang Wub, Fang-RongChangb, Jinn-YuhGuhc,d,∗, Lea-Yea Chuange,∗Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-_-related pathways in MCF-7 cells. Journal of Ethnopharmacology. 137 (2011) 1283-1290.
	In article		View Article  PubMed
[41]	Soheil Zorofchian Moghadamtousi, Hamed Karimian, Elham Rouhollahi, Mohammadjavad Paydar, Mehran Fadaeinasab, Habsah Abdul Kadir. Annona muricataleavesinduceG1 cell cyclearrest and apoptosis through mitochondria-mediated pathwayinhumanHCT-116 and HT-29 colon cancercells Journal of Ethnopharmacology 156 (2014) 277-289.
	In article		View Article  PubMed
[42]	Constant Anatole Pieme, Santosh Guru Kumar, Mireille SylvianeDongmo, Bruno Moukette Moukette1, Fabrice Fekam Boyoum4, Jeanne YonkeuNgogang and Ajit Kumar Saxena. Antiproliferative activity and induction of apoptosis by Annona muricata (Annonaceae) bextract on human cancer cells. Pieme et al. BMC Complementary and Alternative Medicine 2014, 14:516.
	In article		View Article  PubMed
[43]	Yang C1, Gundala SR1, Mukkavilli R2, Vangala S3, Reid MD4, Aneja R5.Synergistic interactions among flavonoids and acetogenins in Graviola (Annona muricata) leaves confer protection against prostate cancer.Carcinogenesis. 2015 Jun;36(6):656-65. doi: 10.1093/carcin/bgv046. Epub 2015 Apr 11.
	In article		View Article
[44]	Wang, L. Q., Min BS, Li Y, Nakamura N, Qin GW, Li CJ, Hattori M.. “Annonaceous acetogenins from the leaves of Annona montana.” Bioorg. Med. Chem. 2002;10(3):561-5.
	In article		View Article
[45]	Woo, M. H., Chung, S. O. & Kim, D. H. “Cis-annonacin and (2,4)-cis-and trans-isoannonacins: cytotoxic monotetrahydrofuran annonaceous acetogenins from the seeds of Annona cherimolia.” Arch. Pharm. Res. 1999; 22(5): 524-8.
	In article		View Article  PubMed
[46]	Kim GS, Zeng L, Alali F, Rogers LL, Wu FE.“Muricoreacin and murihexocin c, mono-tetrahydrofuran acetogenins, from the leaves of Annona muricata.” Phytochemistry1998; 49(2): 565-571.
	In article		View Article
[47]	Zhao GX1, Rieser MJ, Hui YH, Miesbauer LR, Smith DL, McLaughlin JL. “Biologically active acetogenins from stem bark of Asiminatriloba.” Phytochemistry1993; 33(5): 1065-73.
	In article		View Article
[48]	Alali FQ1, Liu XX, McLaughlin JL. “Annonaceous acetogenins: Recent progress.” J. Nat. Prod. 1999; 62(3): 504-540.
	In article		View Article  PubMed
[49]	Morre DJ, de Cabo R, Farley C, Oberlies NH, McLaughlin JL. “Mode of action of bullatacin, a potent antitumor acetogenin: inhibition of NADH oxidase activity of HeLa and HL-60, but not liver, plasma membranes.” Life Sci. 1995; 56(5): 343-8.
	In article		View Article
[50]	Nicholas H. Oberlies, Ching-jer Chang, and Jerry L. McLaughlin. “Structure-activity relationships of diverse annonaceousacetogenins against multidrug resistant human mammary adenocarcinoma (MCF-7/Adr) cells.” J. Med. Chem. 1997; 40(13): 2101-2106
	In article		View Article  PubMed
[51]	González-Coloma A1, Guadaño A, de Inés C, Martínez-Díaz R, Cortes D. “Selective action of acetogenin mitochondrial complex I inhibitors.” Z. Naturforsch2002; 57(11-12): 1028-34.
	In article
[52]	J.B. Minari *, U. Okeke. Chemopreventive effect of Annona muricata on DMBA-induced cell proliferation in the breast tissues of female albino mice. The Egyptian Journal of Medical Human Genetics (2014) 15, 327–334.
	In article		View Article
[53]	Fernandes JV1, Cobucci RN, Jatobá CA, Fernandes TA, de Azevedo JW, de Araújo JM.The role of the mediators of inflammation in cancer development. PatholOncol Res. 2015 Jul;21(3):527-34.
	In article		PubMed
[54]	Jeno Paul, R. Gnanam, R. M. Jayadeepa and L. Arul. Anti-Cancer Activity on Graviola, Exciting Medicinal Plant Extract vs Various Cancer Cell Lines and a Detailed Computational Study on its Potent Anti-Cancerous Leads. Current Topics in Medicinal Chemistry 2013. V.13:1666-1673:8.
	In article
[55]	Jayashree BS, Nigam S, Pai A, Patel HK, Reddy ND, Kumar N, Rao CM. Targets in anticancer research--A review. Indian J Exp Biol. 2015 Aug; 53(8):489-507.
	In article		PubMed
[56]	C.W. Taylor, A.M. Kirby. Cardiac Side-effects From Breast Cancer Radiotherapy. Clinical Oncology 27 (2015) 621-629.
	In article		View Article  PubMed
[57]	Christina H. Ruhlmann, Trine ZeebergIversen, MeenaOkera, Aida Muhic, Gunnar Kristensen Petra Feyer, Olfred Hansen. Multinational study exploring patients’ perceptions of side-effects induced by chemo-radiotherapy Radiother.Oncol.2015.09.014.
	In article