Synergistic Antitumor Effect of a Combination of Paclitaxel and Carboplatin with Nobiletin from Citrus depressa on Non-Small-Cell Lung Cancer Cell Lines

Abstract

Non-small-cell lung carcinomas do not sufficiently respond to cancer chemotherapeutic drugs. Combination effects of cancer chemotherapy drugs (paclitaxel and carboplatin) with nobiletin or powdered Shiikuwasha extract from Citrus depressa were examined by isobologram and combination index analyses. It was demonstrated that the combination generated a synergistic inhibitory effect against the proliferation of the human non-small-cell lung carcinoma cell lines A549 and H460 and that of the two chemotherapy drugs, paclitaxel was responsible for this synergistic effect. Furthermore, the percentage of apoptotic cells was decreased with increasing rates of nobiletin to paclitaxel and carboplatin. These findings were considered to be attributed to the ability of nobiletin to regulate cells in the G₁ phase, which escaped cell death initiated by paclitaxel and carboplatin. An antitumor activity assay showed that this combination significantly suppressed the growth of subcutaneous A549 tumor xenografts in nude mice.

Key words

nobiletin - Citrus depressa - Rutaceae - non-small-cell lung cancer - cancer chemotherapy drug - synergistic effect - A549 cell xenograft

• References

• 1 Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8: 303-306
• 2 Shaw AT, Yasothan U, Kirkpatrick P. Crizotinib. Nat Rev Drug Discov 2011; 10: 897-898
• 3 Janku F, Stewart DJ, Kurzrock R. Targeted therapy in non-small-cell lung cancer – is it becoming a reality?. Nat Rev Clin Oncol 2010; 7: 401-414
• 4 Soda M, Takada S, Takeuchi K, Choi YL, Enomoto M, Ueno T, Haruta H, Hamada T, Yamashita Y, Ishikawa Y, Sugiyama Y, Mano H. Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448: 561-567
• 5 Langer CJ, Leighton JC, Comis RL, OʼDwyer PJ, McAleer CA, Bonjo CA, Engstrom PF, Litwin S, Ozols RF. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol 1995; 13: 1860-1870
• 6 Neijt JP, Engelholm SA, Tuxen MK, Sørensen PG, Hansen M, Sessa C, de Swart CAM, Hirsch FR, Lund B, van Houwelingen HC. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 2000; 18: 3084-3092
• 7 Rathera MA, Bhata BA, Qurishib MA. Multicomponent phytotherapeutic approach gaining momentum: Is the “one drug to fit all” model breaking down?. Phytomedicine 2013; 21: 1-14
• 8 Rooprai HK, Kandanearatachi A, Rucklidge G, Pilkington GJ. Influence of putative antiinvasive agents on matrix metalloproteinase secretion by human neoplastic glia in vitro . Ann N Y Acad Sci 1999; 30: 654-657
• 9 Murakami A, Nakamura Y, Torikai K, Tanaka T, Koshiba T, Koshimizu K, Kuwahara S, Takahashi Y, Ogawa K, Yano M, Tokuda H, Nishino H, Mimaki Y, Sashida Y, Kitanaka S, Ohigashi H. Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res 2000; 60: 5059-5066
• 10 Nakajima A, Yamakuni T, Haraguchi M, Omae N, Song SY, Kato C, Nakagawasai O, Tadano T, Yokosuka A, Mimaki Y, Sashida Y, Ohizumi Y. Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice. J Pharmacol Sci 2007; 105: 122-126
• 11 Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, Tetsu N, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y. Nobiletin, a citrus flavonoid, improves memory impairment and a pathology in a transgenic mouse model of Alzheimerʼs disease. J Pharmacol Exp Ther 2008; 326: 739-744
• 12 Lee YS, Cha BY, Saito K, Yamakawa H, Choi SS, Yamaguchi K, Yonezawa T, Teruya T, Nagai K, Woo JT. Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. Biochem Pharmacol 2010; 79: 1674-1683
• 13 Morley KL, Ferguson PJ, Koropatnick J. Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer Lett 2007; 251: 168-178
• 14 Meiyanto E, Hermawan A, Junedi S, Fitriasari A, Susidarti RA. Nobiletin increased cytotoxic activity of doxorubicin on Mcf-7 cells but not on T47 d cells. Int J Phytomed 2011; 3: 129-137
• 15 Yoshimizu N, Otani Y, Saikawa Y, Takahashi T, Yoshida M, Furukawa T, Kubota T, Kumai K, Tomita T, Kameyama K, Okada Y, Ito A, Kitajima M. Combination effects of nobiletin with CDDP on gastric cancer cells. American Association for Cancer Research Meeting. Proc Amer Assoc Cancer Res 2004; 45: Abstract #838
• 16 Deen DF, Williams ME. Isobologram analysis of X-ray-BCNU interactions in vitro . Radiat Res 1979; 79: 483-491
• 17 Redpath JL. Mechanisms in combination therapy: isobologram analysis and sequencing. Int J Radiat Biol 1980; 38: 355-356
• 18 Altenburger R, Bödeker W, Faust M, Grimme LH. Evaluation of the isobologram method for the assessment of mixtures of chemicals. Combination effect studies with pesticides in algal biotests. Ecotoxicol Environ Saf 1990; 20: 98-114
• 19 Zhao L, Wientjes MG, Au JL. Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin Cancer Res 2004; 10: 7994-8004
• 20 Rixe O, Fojo T. Is cell death a critical end point for anticancer therapies or is cytostasis sufficient?. Clin Cancer Res 2007; 13: 7280-7287
• 21 Kiyokawa S, Hirata Y, Nagaoka Y, Shibano M, Taniguchi M, Yasuda M, Baba K, Uesato S. New orally bioavailable 2-aminobenzamide-type histone deacetylase inhibitor possessing a (2-hydroxyethyl)(4-(thiophen-2-yl)benzyl)amino group. Bioorg Med Chem 2000; 18: 3925-3933
• 22 Komatsu Y, Tomizaki K, Tsukamoto M, Kato T, Nishino N, Sato S, Yamori T, Tsuruo T, Furumai R, Yoshida M, Horinouchi S, Hayashi H. Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. Cancer Res 2001; 61: 4459-4466