The farnesyltransferase inhibitor Lonafarnib induces growth arrest or apoptosis of human lung cancer cells without downregulation of Akt.
Farnesyltransferase inhibitors (FTIs) have been demonstrated to induce growth arrest or apoptosis independent of Ras mutation. Alternatively, Akt has been proposed as a potential target for the FTI's actions. This study investigated whether Lonafarnib was effective in inhibiting the growth of human nonsmall cell lung cancer (NSCLC) cells and elucidated the role of Akt in mediating such growth inhibitory effects. Lonafarnib, at clinical achievable concentration ranges, was effective in inhibiting the growth of 10 NSCLC cell lines, particularly after a prolonged treatment, regardless of Ras mutational status. Lonafarnib arrested cells growth at G(1) or G(2)/M phase in the majority tested cell lines. However it induced apoptosis when cells were cultured in a low serum (0.1%) medium. The majority of NSCLC cell lines expressed undetectable level of phosphorylated Akt (p-Akt). Lonafarnib at up to 10 muM did not decrease either total Akt level or p-Akt level in any of the tested cell lines, even after a 48 h treatment. Unexpectedly, Lonafarnib even increased p-Akt level in one cell line, although it was as sensitive as others to Lonafarnib treatment and underwent G(2)/M arrest. Bovine serum albumin completely rescued cells from Lonafarnib-induced apoptosis in low serum medium, indicating that proteins rather than cytokines or growth factors in serum masks Lonafarnib's pro-apoptotic effect. Therefore, we conclude that Lonafarnib is effective in inhibiting the growth of NSCLC cells either via growth arrest or induction of apoptosis without downregulation of Akt.
Sun
Shi-Yong
SY
Department of Hematology and Oncology, Emory University School of Medicine, 1365-C Clifton Road, C3088, Atlanta, Georgia 30322, USA. shi-yong_sun@emoryhealthcare.org
Zhou
Zhongmei
Z
Wang
Ruoxiang
R
Fu
Haian
H
Khuri
Fadlo R
FR
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D012710:Serum Albumin, Bovine; C494918:AKT1 protein, human; C115354:lonafarnib; D003986:Dibenzocycloheptenes