Limonene and BEZ 235 inhibits growth of COLO-320 and HCT-116 colon cancer cells

Raja Ratna Reddy yakkanti, P Chandra Sekhar, K Bharath Nandhan Reddy, S Ramamoorthy, S Ranga Suresh, T Yasodha Lakshmi, Mani Rajesh, C Damodar Reddy

DOI: http://dx.doi.org/10.5138/09750215.1919

Abstract


D-Limonene is a dietary monoterpene with significant anticancer activity against many cancer types in preclinical and clinical studies. The study is designed to investigate synergistic anticancer effects of limonene and BEZ235 combination in COLO-320 and HCT-116 colon cancer cells. Cells were treated with both the drugs alone and in combination and the effects on cell viability; cell migration and clonogenic potential were examined. Results show that both drugs exhibited dose and time dependant cytotoxicity on the cell lines tested. CompuSyn analysis of the drug combination effects revealed the strong synergistic interaction of the combination. Our results also indicate that COLO-320 cells were more sensitive for anticancer effects of the drugs than HCT-116 cells. The presence of Ras and PI3K mutations in HCT-116 cells could possibly be one of the main reasons for the observed outcome as compared to the wild type expressions of them in COLO-320 cells.


Keywords


Colorectal cancer, limonene, BEZ235, Ras, PI3K

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References


. American Cancer Society. Cancer Facts & Figures. 2015. [2]. Burt RW, DiSario JA, Cannon-Albright L. Genetics of colon cancer: impact of inheritance on colon cancer risk. Annu Rev Med. 1995; 46: 371-379. [3]. Ponz de Leon M, Sassatelli R, Benatti P, Roncucci L. Identification of hereditary nonpolyposis colorectal cancer in the general population: the 6-year experience of a population-based registry. Cancer. 1993; 71: 3493-3501. [4]. Stewart SL, Wike JM, Kato I, Lewis DR, Michaud F. A population-based study of colorectal cancer histology in the United States 1998-2001. Cancer. 2006; 107: 1128-1141. [5]. Rodriguez-Viciana P, Warne PH, Dhand R. Phosphatidylinositol-3-OH kinase as a direct target of ras. Nature. 1994; 370: 527-32. [6]. Baba Y, Nosho K, Shima K, Hayashi M, Meyerhardt JA. Phosphorylated AKT expression is associated with PIK3CA mutation, low stage, and favorable outcome in 717 colorectal cancers. Cancer. 2011; 117: 1399-1408. [7]. Igimi H, Hisatsugu T, Nishimura M. The use of d-limonene preparation as a dissolving agent of gallstones. Am J Dig Dis. 1976; 21: 926-939. [8]. Wilkins J Jr. Method for treating gastrointestinal disorder. U.S. Patent (642045). 2002. [9]. Del Toro Arreola S, Flores Torales E, Torres Lozano C, Del Toro Arreola A, Tostado Pelayo K, Guadalupe Ramirez Duenas M, Daneri Navarro A. Effect of D-limonene on immune response in BALB/c mice with lymphoma. Int Immunopharmacol. 2005; 5: 829-838. [10]. Maltzman TH, Hurt LM, Elson CE, Tanner MA, Gould MN. The prevention of nitrosomethylurea-induced mammary tumors by D-limonene and orange oil. Carcinogenesis. 1989; 10: 781-783. [11]. Lu XG, Zhan LB, Feng BA, Qu MY, Yu LH, Xie JH. Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by D-limonene. World J Gastroenterol. 2004; 10: 2140-2144. [12]. Kaji I, Tatsuta M, Iishi H, Baba M, Inoue A, Kasugai H. Inhibition by D-limonene of experimental hepatocarcinogenesis in Sprague-Dawley rats does not involve p21(ras) plasma membrane association. Int J Cancer. 2001; 93: 441-444. [13]. Raphael TJ, Kuttan G. Effect of naturally occurring monoterpenes carvone, limonene and perillic acid in the inhibition of experimental lung metastasis induced by B16F-10 melanoma cells. J Exp Clin Cancer Res. 2003; 22: 419-424. [14]. Rabi T, Bishayee A. D-Limonene sensitizes docetaxel induced cytotoxicity in human prostate cancer cells: generation of reactive oxygen species and induction of apoptosis. J Carcinog. 2009; 8:9. [15]. Kawamori T, Tanaka T, Hirose Y, Ohnishi M, Mori H. Inhibitory effects of d- limonene on the development of colonic aberrant crypt foci induced by azoxymethane in F344 rats. Carcinogenesis. 1996; 17: 369-372. [16]. Cao P, Maira S-M, Garcia-Echeverria C, Hedley DW. Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br J Cancer. 2009; 100: 1267-1276. [17]. Brachmann SM, Hofmann I, Schnell C. Specific apoptosis induction by the dual PI3K/ MTOR inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci USA. 2009; 106: 22299-304. [18]. Manara MC, Nicoletti G, Zambelli D. NVP- BEZ235 as a new therapeutic option for sarcomas. Clin Cancer Res. 2010; 16: 530-40. [19]. Areumnuri Kim, Jung-Eun Lee, Seung-Sook Lee, Cherin Kim, Sun-Joo Lee, Won-Suk Jang, Sunhoo Park. Coexistent mutations of KRAS and PIK3CA affect the efficacy of NVP-BEZ235, a dual PI3K/mTOR inhibitor, in regulating the PI3K/mTOR pathway in colorectal cancer. Int. J. Cancer. 2013; 133: 984-996. [20]. Roper P, Drewinko B. Comparison of in vitro methods to determine drug-induced cell lethality. Cancer Res. 1975; 26: 2182-2188. [21]. Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacological Reviews. 2006; 58: 621-681. [22]. Karapetis CS, Khambata Ford S, Jonker DJ, O Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008; 359: 1757-1765. [23]. Vigushin DM, Poon GK, Boddy A. Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee. Cancer Chemother Pharmacol. 1998; 42: 111-117.


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