[Sequence-dependent Effect of Triptolide with Gefitinib on the Proliferation and Apoptosis of Lung Adenocarcinoma Cell H1975].
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show promising therapeutic effects in patients with advanced non-small cell lung cancer (NSCLC). However, despite an initial response to TKIs treatment among responsive patients, most inevitably acquire resistance after a progression-free period of about 10 months. The percentage of T790M in TKI acquired-resistant patients in most studies is around 50%. The aim of this study is to assess the effects of the sequential administration of triptolide and geftinib on cell proliferation and apoptosis of lung adenocarcinoma cell H1975.


METHODS
A MTT assay was used to measure cell proliferation. The potency of the sequential administration of triptolide and geftinib were determined by isobolograms and combination index (CI). Cell apoptosis and cycle distribution were detected by flow cytometry. The Hoechst 33258 method was used to observe the apoptotic morphology. Chemical colorimetric luminescence was used to measure the caspase activity.


RESULTS
The results of isobolograms and CI showed that the sequential administration of triptolide following geftinib remarkably inhibited cell proliferation and cell apoptosis compared with other sequential administration models. The cycle distribution results indicated that sequential triptolide administration following geftinib blocked the cells in the G2/M phase but not in the G0/G1 phase. The activation of the Caspase-9/Caspase-3 cascade was mainly involved in the apoptotic pathway of lung adenocarcinoma cell H1975 in all sequential administration models.


CONCLUSIONS
The triptolide administration following geftinib might be a new therapeutic strategy for lung cancer with T790M mutation after having EGFR-TKIs resistance. .
Department of Pharmacy, Bengbu Medical College, Bengbu 233000, China.
Xinyu
X
Zhang
Department of Pharmacy, the Affiliated Hospital of Chinese PLA Hospital, Beijing 100853, China.
Guiyang
G
Liu
Department of Pharmacy, Bengbu Medical College, Bengbu 233000, China.
Hao
H
Liu
Department of Pharmacy, Bengbu Medical College, Bengbu 233000, China.
Tao
T
Ma
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D010616:Phenanthrenes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C001899:triptolide; D066246:ErbB Receptors; D000077156:Gefitinib