title: Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells.
abstract: AKT is the frequently overexpressed and constitutively active kinase within NSCLC cells and recognized as a promising target for NSCLC treatment. However, AKT inhibition relieves the feedback inhibition of upstream receptor tyrosine kinases (RTKs) that may weaken the efficiency of AKT inhibitors. Platycodin D (PD), isolated from widely-used traditional Chinese medicine Platycodonis Radix, is now found to remarkably enhance the anti-proliferative effect of AKT inhibitors. In this study, combinatorial activity of AKT inhibitor MK2206 and PD on cell proliferation, apoptosis and related signaling were disclosed. Long-term AKT inhibition induced up-regulation of RTKs, including EGFR and HER-2. Co-treatment of MK2206 with PD could abolish this feedback survival through decrease of EGFR, HER-2, and p-AKT, and profound inhibition of 4E-BP1, leading to an amplified anti-proliferative and apoptotic activity in NSCLC cells. Similarly, feedback activation in response to reduction of AKT expression by small interfering RNA (siRNA) was also blocked by PD and apoptotic effect was further enhanced. Thus, PD potentiated proliferative inhibition and apoptotic induction of both AKT inhibitor and siRNA. These findings also reveal the limitations of suppressing feedback-regulated pathways by monotherapy and establish a mechanistic rationale for a novel combination approach targeting AKT for the treatment of NSCLC.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Dik Lung
authors.initials: DL
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Chung Hang
authors.initials: CH
authors.lastname: Leung
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Jin Jian
authors.initials: JJ
authors.lastname: Lu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D025461:Feedback, Physiological; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D012503:Saponins / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D012503:Saponins; D014315:Triterpenes; C108953:platycodin D; D051057:Proto-Oncogene Proteins c-akt