PT  - JOURNAL ARTICLE
AU  - Haiyan Ge
AU  - Songshi Ni
AU  - Jiaxian Ou
AU  - Xiaocong Fang
AU  - Yuanlin Song
AU  - Chunxue Bai
TI  - Glucocorticoid reduces pemetrexed sensitivity by mediating senescence-associated secretory phenotype in Bcl-2 dependent manner in non-small-cell lung cancer
DP  - 2013 Sep 01
TA  - European Respiratory Journal
PG  - P3115
VI  - 42
IP  - Suppl 57
4099  - http://erj.ersjournals.com/content/42/Suppl_57/P3115.short
4100  - http://erj.ersjournals.com/content/42/Suppl_57/P3115.full
SO  - Eur Respir J2013 Sep 01; 42
AB  - Rationale: Pemetrexed (PEM), a novel and multitargeted antifolate, has been used as an antineoplastic agent for non-small-cell lung cancer (NSCLC) and pleural mesothelioma. Although glucocorticoids (such as dexamethasone, DEX) are recommended to be co-administered with PEM during the chemotherapy to reduce toxicity, it is not clear yet whether DEX co-administration could affect PEM efficacy or not on chemotherapy.Methods: We used established NSCLC cell lines (H1650, A549, H2228 and H292) and examined the effects of DEX on PEM sensitivity in vitro and in xenograft models.Results: We found that DEX co-administration could reduce sensitivity to PEM and have high capacity for tumor invasion and metastasis. Meanwhile, DEX co-adminstration weakened senescence growth arrest, such as altered secretions of proinflammatory and mitogenic cytokines, reminiscent of a senescence associate secretory phenotype (SASP). Furthermore, we demonstrated that DEX co-administration enhanced ability of self-renewal, clonogenicity and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). In addition, we found that expression of Bcl-2 was increased with DEX co-administration. Knockdown expression of Bcl-2 inhibited cell growth and clonogenicity in DEX co-administration group.Conclusion: DEX might suppress the antitumor activity of PEM through alterd SASP level, thus changing self-renewal ability in Bcl-2 dependent manner. Extra caution need to be required when PEM and DEX were jointly adminstered in NSCLC patients chemotherapy.