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.

[1]  M. Rather,et al.  Multicomponent phytotherapeutic approach gaining momentum: Is the "one drug to fit all" model breaking down? , 2013, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[2]  R. Kurzrock,et al.  Targeted therapy in non-small-cell lung cancer—is it becoming a reality? , 2010, Nature Reviews Clinical Oncology.

[3]  B. Cha,et al.  Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. , 2010, Biochemical pharmacology.

[4]  S. Uesato,et al.  New orally bioavailable 2-aminobenzamide-type histone deacetylase inhibitor possessing a (2-hydroxyethyl)(4-(thiophen-2-yl)benzyl)amino group. , 2010, Bioorganic & medicinal chemistry.

[5]  R. Shin,et al.  Nobiletin, a Citrus Flavonoid, Improves Memory Impairment and Aβ Pathology in a Transgenic Mouse Model of Alzheimer's Disease , 2008, Journal of Pharmacology and Experimental Therapeutics.

[6]  T. Fojo,et al.  Is Cell Death a Critical End Point for Anticancer Therapies or Is Cytostasis Sufficient? , 2007, Clinical Cancer Research.

[7]  H. Aburatani,et al.  Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer , 2007, Nature.

[8]  J. Koropatnick,et al.  Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. , 2007, Cancer letters.

[9]  Y. Okada,et al.  Combination effects of nobiletin with CDDP on gastric cancer cells , 2004 .

[10]  R. Pazdur,et al.  FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. , 2003, The oncologist.

[11]  H. V. van Houwelingen,et al.  Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  A. Murakami,et al.  Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. , 2000, Cancer research.

[13]  G. Pilkington,et al.  Influence of Putative Antiinvasive Agents on Matrix Metalloproteinase Secretion by Human Neoplastic Glia in Vitro , 1999, Annals of the New York Academy of Sciences.

[14]  R. Ozols,et al.  Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  M. Faust,et al.  Evaluation of the isobologram method for the assessment of mixtures of chemicals. Combination effect studies with pesticides in algal biotests. , 1990, Ecotoxicology and environmental safety.

[16]  D. Deen,et al.  Isobologram analysis of X-ray--BCNU interactions in vitro. , 1979, Radiation research.

[17]  E. Meiyanto,et al.  Nobiletin Increased Cytotoxic Activity Of Doxorubicin On Mcf-7 Cells But Not On T47d Cells , 2011 .

[18]  Si-young Song,et al.  Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice. , 2007, Journal of pharmacological sciences.

[19]  T. Tsuruo,et al.  Activity Synthetic Histone Deacetylase Inhibitor with Antitumor Cyclic Hydroxamic-acid-containing Peptide 31 , a Potent Updated Version , 2001 .

[20]  J. Redpath.  Mechanisms in combination therapy: isobologram analysis and sequencing. , 1980, International journal of radiation biology and related studies in physics, chemistry, and medicine.