Portal de Periódicos da CAPES

Improved efficacy with sequential use of histone deacetylase inhibitor, LAQ824, with common chemotherapeutic agents in head and neck squamous carcinoma cell lines

2005; American Association for Cancer Research; Volume: 65; Linguagem: Inglês

1538-7445

Youngju Kim, Eun Kyung Bae, Kwang‐Sung Ahn, Jong-Seok Lee, Seonyang Park, Byoung Kook Kim, Sung‐Soo Yoon,

Acute Myeloid Leukemia Research

Proc Amer Assoc Cancer Res, Volume 46, 2005 5097 Imatinib mesylate (Glivec, Gleevec, STI571) is highly effective in patients with chronic myeloid leukemia (CML). Despite high rates of hematologic and cytogenetic responses to Glivec therapy, the emergence of resistance to Glivec has been recognized as a major problem in the treatment of CML. To investigate the mechanisms of resistance to Glivec, Glivec resistant cell line (K562 derivatives) was established. Using those cell line, we found that SK-7068, one of HDAC inhibitors, did enhance the apoptosis with increasing levels of cytochrome C, caspase 7, and caspase 3. In additions, the expression levels of STAT1 and STAT5 was down-regulated. Based on our findings, combined treatment of SK-7068 and Glivec could be novel therapy for CML being resistant to Glivec. To investigate the effect of combined treatment, the expression levels of pro-apoptotic genes related genes, such as Bcl-2 family, caspase-3, and its cell cycle proteins, such as p53, p21, and cyclin D1, CDKs and PCNA were examined by western analysis. Our results showed that Bcl-2, -XL, and Bid were more down-regulated with combined treatment compared with single treatment controls (either Glivec or curcumin alone). Under the same conditions, the activity of caspase 3 was dramatically increased. Increasing levels of p21 expression was found in combined treatment whereas its expression was not detected when K562 cells were treated with either SK-7068 or Glivec. Our results indicated that increasing level of p21 expression may enhance the apoptosis. For further investigation of the genes affected by combination therapy, DNA chip analysis was performed. The expression of candidate genes, which we selected in chip analysis, was confirmed using real-time PCR. Our result indicated that apoptosis related genes were up-regulated and were down-regulated. Also, several genes (protein phosphatase 2C, ERBB3, JARID2, INSIG1, RNF41, RGSIPIP1, PRSS12, HUMPPA, PDCD4)) were more down-regulated in combined treatment, showing 2-fold difference. Those genes may be associated with the progression of chronic myeloid leukemia. Taken together, our data suggested that combined treatment with SK-7068 could be effective to overcome the problems of Imatinib mesylate therapy.