title: Suppression of MAPK Signaling and Reversal of mTOR-Dependent MDR1-Associated Multidrug Resistance by 21α-Methylmelianodiol in Lung Cancer Cells.
abstract: Lung cancer is the leading cause of cancer-related deaths worldwide and remains the most prevalent. Interplay between PI3K/AMPK/AKT and MAPK pathways is a crucial effector in lung cancer growth and progression. These signals transduction protein kinases serve as good therapeutic targets for non-small cell lung cancer (NSCLC) which comprises up to 90% of lung cancers. Here, we described whether 21α-Methylmelianodiol (21α-MMD), an active triterpenoid derivative of Poncirus trifoliate, can display anticancer properties by regulating these signals and modulate the occurrence of multidrug resistance in NSCLC cells. We found that 21α-MMD inhibited the growth and colony formation of lung cancer cells without affecting the normal lung cell phenotype. 21α-MMD also abrogated the metastatic activity of lung cancer cells through the inhibition of cell migration and invasion, and induced G0/G1 cell cycle arrest with increased intracellular ROS generation and loss of mitochondrial membrane integrity. 21α-MMD regulated the expressions of PI3K/AKT/AMPK and MAPK signaling which drove us to further evaluate its activity on multidrug resistance (MDR) in lung cancer cells by specifying on P-glycoprotein (P-gp)/MDR1-association. Employing the established paclitaxel-resistant A549 cells (A549-PacR), we further found that 21α-MMD induced a MDR reversal activity through the inhibition of P-gp/MDR1 expressions, function, and transcription with regained paclitaxel sensitivity which might dependently correlate to the regulation of PI3K/mTOR signaling pathway. Taken together, these findings demonstrate, for the first time, the mechanistic evaluation in vitro of 21α-MMD displaying growth-inhibiting potential with influence on MDR reversal in human lung cancer cells.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Mark Borris Docdoc
authors.initials: MB
authors.lastname: Aldonza
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Song
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Won Kyung
authors.initials: WK
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Jedo
authors.initials: J
authors.lastname: Oh
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Yoonho
authors.initials: Y
authors.lastname: Shin
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongbuk, Korea.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004338:Drug Combinations; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009361:Neoplasm Invasiveness / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D055372:AMP-Activated Protein Kinases; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004338:Drug Combinations; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; C525645:21-methylmelianodiol; C546842:MTOR protein, human