title: Curcumin potentiates the ability of sunitinib to eliminate the VHL-lacking renal cancer cells 786-O: rapid inhibition of Rb phosphorylation as a preamble to cyclin D1 inhibition.
abstract: Curcumin, an important component of the culinary spice turmeric, has been shown to harbor anticancer properties against a wide range of cancer cells with minimal toxicity toward normal cells. Two general tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib are currently used in treating renal cancer. Though the use of these TKIs has significantly improved survival, both elicit distressing side effects, limiting their long-term use. We tested the activity of sunitinib and sorafenib to eliminate 786-O renal cancer cells and the efficacy of curcumin to enhance this process. A four-fold decrease in the IC50 of sunitinib, from 4.5 μM to 1.2 μM, was observed in the presence of 20-μM curcumin. However, curcumin did not potentiate the activity of sorafenib. The sunitinib-curcumin (SunC) combination sharply inhibited hyperphosphorylation of the tumor suppressor protein Rb within 8 hours of SunC treatment. Although the levels of cyclin D1 did not change in 8 hours, its expression was dramatically inhibited after 24 hours of SunC exposure. Since curcumin is known to inhibit the cyclin D1-dependent G1/S-phase kinase CDK4 and the cyclin B-dependent G2/M-phase kinase CDK1 that catalyze phosphorylation-mediated inactivation of Rb, our results indicate that SunC containing a lower dose of sunitinib would be effective in restoring the tumor suppressor activity of Rb, thereby truncating cell cycle and triggering cell death. Our results submit the possibility of using SunC as an effective antitumor formulation to reduce the dose and risk of adverse effects of sunitinib.
authors.forename: Priya Ranjan
authors.initials: PR
authors.lastname: Debata
authors.forename: Sultana
authors.initials: S
authors.lastname: Begum
authors.forename: Anita
authors.initials: A
authors.lastname: Mata
authors.forename: Oksana
authors.initials: O
authors.lastname: Genzer
authors.forename: Morton J
authors.initials: MJ
authors.lastname: Kleiner
authors.forename: Probal
authors.initials: P
authors.lastname: Banerjee
authors.affiliation: Department of Chemistry and the Center for Developmental Neuroscience, The City University of New York at The College of Staten Island, Staten Island, NY, 10314, USA. probal.banerjee@csi.cuny.edu.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Castellanos
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077157:Sorafenib; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D010671:Phenylurea Compounds; D011758:Pyrroles; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D009536:Niacinamide; D000077157:Sorafenib; D016203:CDC2 Protein Kinase; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D003474:Curcumin; D000077210:Sunitinib