Induction of apoptosis in A549 human lung cancer cells by all-trans retinoic acid incorporated in DOTAP/cholesterol liposomes.
All-trans retinoic acid (ATRA) has been shown to exert anti-cancer activities in a number of types of cancer cells. However, it has been reported that many NSCLC exhibited resistance to ATRA treatment. In the present study, we hypothesized that intracellular delivery of ATRA would overcome the ATRA resistance in A549 cells. Here, we investigated the induction of apoptosis by ATRA incorporated in cationic liposomes composed of DOTAP/cholesterol in A549 human lung cancer cells, which are insensitive (resistant) to the growth inhibitory effects of ATRA. The zeta potentials of DOTAP/cholesterol liposomes and DSPC/cholesterol liposomes were about +50 and -3 mV. In A549 cells, [(3)H]ATRA incorporated in DOTAP liposomes showed increased cellular association compared with [(3)H]ATRA or [(3)H]ATRA incorporated in DSPC/cholesterol liposomes. ATRA incorporated in DOTAP/cholesterol liposomes showed much higher cytotoxic effects and apoptosis-inducing activity compared with ATRA or ATRA incorporated in DSPC/cholesterol liposomes. The enhanced expression of TIG3 mRNA tumor suppressor gene by ATRA incorporation into DOTAP/cholesterol liposomes might partly explain the mechanism of enhanced cytotoxicity and/or apoptosis. These observations provide valuable information to help in the design of differentiation therapy by ATRA in non-small cell lung carcinoma.
Kawakami
Shigeru
S
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Suzuki
Sachiko
S
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002784:Cholesterol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014212:Tretinoin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D014212:Tretinoin; D002784:Cholesterol; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane