The Raf kinase inhibitor BAY 43-9006 reduces cellular uptake of platinum compounds and cytotoxicity in human colorectal carcinoma cell lines.
Raf kinase plays a central role in oncogenic signaling and acts as a downstream effector of Ras in the extracellular signal-regulated (ERK) kinase pathway. BAY 43-9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-beta. The present study evaluates the effects of combining BAY and platinum derivatives on human colorectal cancer cells using different incubation protocols. Our data show that the combination of oxaliplatin or cisplatin with BAY results in marked antagonism irrespective of the used application schedule. Furthermore, BAY abrogates the cisplatin-induced G2 arrest as well as the G1 arrest induced by oxaliplatin. BAY alone arrests cancer cells in their current cell cycle phase and affects cell cycle regulative genes. Specifically, BAY reduced the protein expression of p21Cip1 as well as cyclin D1, and inhibits the expression of cdc2 (cdk1). Utilizing atom absorption spectrometry, BAY significantly reduced cellular uptake of platinum compounds and thereby the generation of DNA adducts. Taken together, co-incubation with BAY results in reduced cellular uptake of platinum compounds and consecutively reduced generation of DNA adducts, and eventually decreased cellular cytotoxicity in human colorectal cancer cells. Our results indicate that the Raf kinase inhibitor BAY 43-9006 might also directly or indirectly interact with platinum transporter proteins in vitro.
Heim
Martina
M
Department of Internal Medicine and Medical Oncology, West German Cancer Centre, University Medical School of Essen, Essen, Germany.
Scharifi
Mariam
M
Zisowsky
Jochen
J
Jaehde
Ulrich
U
Voliotis
Dimitris
D
Seeber
Siegfried
S
Strumberg
Dirk
D
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018736:DNA Adducts / Q000037:antagonists & inhibitors; D004336:Drug Antagonism; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010671:Phenylurea Compounds; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077157:Sorafenib; D048490:raf Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D011725:Pyridines; C431073:oxiplatin; D019938:Cyclin D1; D009536:Niacinamide; D000077157:Sorafenib; D048490:raf Kinases; D002945:Cisplatin