Tag Archives: Tipifarnib

We previously reported the establishment and characteristics of a DXM-resistant Tipifarnib

We previously reported the establishment and characteristics of a DXM-resistant Tipifarnib cell line (7TD1-DXM) generated from the IL6-dependent mouse B cell hybridoma 7 cell line. on normal haematopoiesis [47]. Although AG490 could inhibit the cell growth of 7TD1-DXM cells it could not induce apoptosis in these cells (Fig. 3). However AG490 could inhibit cell growth and induce apoptosis in 7TD1-WD-90 cells. More importantly it greatly potentiated the apoptotic effect induced by DXM in 7TD1-WD-90 cells but not in 7TD1-DXM cells (Fig. 3). The results suggested that JAK/STAT pathway may also be important in regulating cell growth and survival in 7TD1-WD-90 cells. Additionally we examined the expression of total JAK2 and phosphorylated JAK2 and total STAT3 and phosphoryated Tipifarnib STAT3 after DXM IL-6 and AG490 treatment. We have previously showed that 50 μM of AG490 could completely block the phosphorylation in the parent 7TD1 cells while STAT3 was constitutively active in the DXM resistant 7TD1-DXM cells [44]. In the present study we observed that AG490 (50 μM) significantly inhibited the expression of phosphorylated JAK2 and phosphorylated STAT3 in the 7TD1-WD-90 cells to some extends but not in 7TD1-DXM Tipifarnib cells. The data suggest that JAK2/STAT3 signaling pathway maybe changed in the 7TD1-WD-90 cells and IL-6 mediated JAK2/STAT3 signaling pathway may at least in part contribute to the reversion of DXM resistance following DXM withdrawal for 90 days in 7TD1-DXM cells (Fig. 4). In addition we measured the expression of JAK2 and phosphorylated JAK2 STAT3 and phosphorylated STAT3 after treating both cell lines with the combination of DXM and AG490 and we could not detect significant change in the expression of these proteins compared with AG490 alone (data not shown). This suggested that DXM did not add any additional inhibitory effects on the JAK2/STAT3 FJH1 signaling pathway compared with by AG490 alone. Previous studies already showed the benefits of withdrawing therapeutic agents to prevent drug induced toxicity and/or to reverse drug resistance. Some chemotherapy agents such as paclitaxe cisplatin and methotrexate could induce neurotoxicity but neurons were able to recover after termination of drug treatment [48]. Macrolide antibiotics could reverse anticancer drug resistance such as vinblastine on leukemia cells [49]. Withdrawal of sex steroid reversed therapy related defects in bone marrow lymphopoiesis [50]. In this study we demonstrate that withdrawing DXM for 90-150 days could near or completely reverse DXM resistant in 7TD1-DXM cells. We also revealed that IL-6 and JAK2/STAT3 pathway may play important roles in the DXM withdrawn cells. Microarray analysis showed that histone deacetylase 3 (HDAC3) was up-regulated in response to IL-6 treatment in 7TD1 cells. We evaluated the effects of two structurally different histone deacetylase inhibitors (HDACi) Suberoylanilide Hydroxamic Acid (SAHA) and Sodium Butyrate (NaB) on proliferation and apoptosis in dexamethasone sensitive resistant and withdrawn 7TD1 cell lines. We found that inhibition of HDAC3 can enhance the sensitivity of 7TD1 multiple myeloma cells to DXM. The data may suggest that the change of the sensitivity to chemotherapy agents may also due to some genetic changes (unpublished data). For patients with MM the average age of patients is about 70 years old and the 5 year survival rate is still relatively very low. DXM is one of the first line chemotherapy choices to treat MM and the drug resistance is a major problem leading to the failure of the therapy. This study provides some information for DXM treatment in patients with MM. Patients with MM may discontinue DXM treatment for a period of time when DXM resistance occurred. The patients may become sensitive to DXM and resume DXM treatment again after termination of the treatment for certain times. In brief this study demonstrates that withdrawing DXM for 90 days or longer can restore the sensitivity of DXM in induction of cytotoxicity and apoptosis in DXM resistant 7TD1-DXM cells near to that of the parent 7TD1 cells. There are different effects of IL-6 and AG490 on cell growth inhibition and apoptosis in 7TD1-DXM and 7TD1-WD cells. It may have potential implication for DXM in treatment of MM clinically. Acknowledgments The authors would like to give our thanks to Saini Ashwani for technical assistance and to Dr. Matthew Ndonwi for his critical review of this manuscript. Grants support This work Tipifarnib was.