Biomarkers of Anticancer Activity of R115777 (Tipifarnib, Zarnestra™) in Human Breast Cancer Models In Vitro

• Published in: Anticancer research Vol. 25; no. 5; pp. 3215 - 3223
• Main Authors: IZBICKA, Elzbieta, CAMPOS, David, CARRIZALES, Gilbert, PATNAIK, Amita
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.09.2005
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Biomarkers, Tumor - metabolism; Breast Neoplasms - blood supply; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Carrier Proteins - metabolism; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line, Tumor; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Farnesyltranstransferase; Heat-Shock Proteins - metabolism; HSP40 Heat-Shock Proteins; Humans; MAP Kinase Signaling System - drug effects; Medical sciences; Neovascularization, Pathologic - metabolism; Paclitaxel - administration & dosage; Paclitaxel - pharmacology; Protein Prenylation - drug effects; Quinolones - administration & dosage; Quinolones - pharmacology; Receptor, ErbB-2 - biosynthesis; rhoB GTP-Binding Protein - metabolism; Tumors; Antineoplastic agent; Human; Enzyme; Farnesyltransferase inhibitor; Ras; Transferases; Biological marker; Activity; Tipifarnib; Breast cancer; Malignant tumor; Farnesyl-diphosphate farnesyltransferase; In vitro; Mammary gland diseases; Cancerology; R115777; Inhibitor; Models
• ISSN: 0250-7005; 1791-7530

Background: Farnesyltransferase inhibitor R115777 (Tipifarnib, Zarnestra™) is active in breast cancer, but its efficacy in drug combinations has not been extensively investigated. Materials and Methods: The activity of R115777 and paclitaxel, alone and in combination, was studied in the human breast cancer cell lines, BT-474 (overexpressed HER2/neu) and MDA-MB-231 (low HER2/neu), with cell viability and biomarkers for farnesylation (HDJ-2, Rho B), tumor growth (Raf/MEK/ERK), survival (PI3K/Akt) and angiogenesis (VEGF, FGF-2, MMP-1, MMP-2, MMP-9) as the endpoints. Results: The drug combination resulted in additive cytotoxicity. R115777 ± paclitaxel inhibited HDJ-2 farnesylation, up-regulated RhoB, transiently lowered (P)ERK/ERK and (P)Akt/Akt, reduced Raf-1 and MEK, and inhibited secretion of VEGF and MMP-1. Conclusion: The effect of R115777 on prenylation biomarkers is consistent with its mechanism of action. The drug interfered with tumor growth, survival and angiogenesis pathways in breast cancer models with low or overexpressed HER2/neu receptor. The combination of R115777 with paclitaxel might offer clinical advantage over monotherapies.