Synergistic cell killing by concomitant treatment of lung cancer cell line with arsenic trioxide and histone deacetylase inhibitor

• Main Authors: Ju-Hsien Yao, 姚如仙
• Other Authors: Te-Chang Lee
• Format: Others
• Language: zh-TW
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/07575917175648819821

碩士 === 國立陽明大學 === 藥理學研究所 === 96 === The efficacy of arsenic trioxide（ATO, Trisenox®）against acute promyelocytic leukemia（APL）and relapsed acute promyelocytic leukemia has been well-documented. ATO has been approved by Food and Drug Administration（FDA）on September 2000 for treatment of relapsed APL. The mechanisms of ATO in cancer therapy include modulation of promyelocytic leukemia（PML）and promyelocytic leukemia-retinoic acid receptor-α（PML-RARα）, induction of apoptosis and cell cycle arrest, and inhibition of cell proliferation. Suberoylanilide hydroxamic acid（SAHA, Vorinostat®）, a histone deacetylase inhibitor, regulates gene or protein expression via histone dependent or independent pathway, and hence results in apoptosis, cell cycle arrest, and differentiation. SAHA has been approved by FDA for treatment of cutaneous T-cell lymphoma（CTCL）. The objective of this study was to investigate whether ATO and SAHA could act in concert to enhance the cytotoxic activity in cancer cells and to examine possible mechanisms. The results showed that combined treatment with ATO and SAHA resulted in synergistic increased cytotoxicity and apoptosis in non-small cell lung carcinoma H1299 cells. Treatment of H1299 cell with ATO alone induced significant DNA damage and the expression of cyclin dependent kinase inhibitors（CDKIs）—p21, which led to G2/M arrest and subsequent apoptosis and senescence. On the other hand, SAHA by itself did not cause DNA damage but induced p21 expression, inhibited the checkpoint kinase（CHK）—CHK1 expression, and subsequent G1 arrest, apoptosis and senescence in H1299 cells. In combination, ATO and SAHA caused DNA damage and resulted in G2/M arrest at 24 h, inhibited the CHK1 and CHK2 expression, which renders DNA damaged cells progressing into G1 phase. Furthermore, a large amount of p21 was induced by combined treatment with ATO and SAHA. Subsequently, apoptosis was significantly enhanced, but senescence was decreased. Accordingly, the synergistic cytotoxicity induced by ATO and SAHA combination may be due to the induction of a large amount of p21 and hence resulted in enhanced apoptosis.