Atorvastatin sensitizes human non-small cell lung carcinomas to carboplatin via suppression of AKT activation and upregulation of TIMP-1.
Platinum-based chemotherapy is the standard treatment for advanced non-small-cell lung carcinomas (NSCLCs). However, the antitumoral effect of carboplatin displays unsatisfactory in NSCLCs treatment due to the AKT pathway-mediated carboplatin insensitive in NSCLCs treatment. Previous studies have shown that statins have antitumor activity, but it is unknown whether atorvastatin can reverse carboplatin resistance in lung cancer. Treatment with atorvastatin and carboplatin reduced the growth of xenograft A549 tumors in nude mice and enhanced the survival rate compared with carboplatin alone. Atorvastatin in combination with carboplatin had stronger effects on growth inhibition and apoptosis of NSCLC than either agent used individually. Carboplatin conferred anti-invasive effect in NSCLC cells mainly through inhibition of AKT activity and resultant upregulation of TIMP-1. However, the inhibitory effect on AKT activity by carboplatin was short-term. Additional atorvastatin administration resulted in synergistic inhibition of NSCLC cell invasion and stimulation of TIMP-1 expression with carboplatin through stronger and persistent inhibition of AKT activity both in vivo and in vitro. The synergy of atorvastatin and carboplatin was confirmed using another human lung carcinoma cell line (H1299). Altogether, our data demonstrate that atorvastatin may overcome carboplatin resistance in lung cancer by suppressing AKT activity and upregulating TIMP-1. A combination of atorvastatin and carboplatin may be an effective strategy in clinical therapy against NSCLCs.
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University and Institute of System Biomedicine, Peking University, Beijing 100191, China.
Jie
J
Chen
Tian
T
Lan
Jincai
J
Hou
Jingjie
J
Zhang
Yu
Y
An
Lu
L
Tie
Yan
Y
Pan
Jicheng
J
Liu
Xuejun
X
Li
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D016190:Carboplatin / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000819:agonists* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D004338:Drug Combinations; D006538:Heptanoic Acids; D011758:Pyrroles; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D000069059:Atorvastatin; D016190:Carboplatin; D051057:Proto-Oncogene Proteins c-akt