These findings indicate that upregulation of ERK activity may be a potential mechanism for BTZ resistance. MEK/ERK pathway is activated in aggressive CKS1B-overexpressing plasma cell myeloma cells. Higher expression levels of p-ERK in human prostate cancer samples were associated with tumor progression. Hyperactivation of the MAPK pathway has also been implicated in the development of neurofibromatosis type Vemurafenib 1-associated leukemia. Our findings are consistent with these previous reports. We further showed that resistance to BTZ can be reversed by PD98059 and U0126, suggesting that MEK/ERK pathway may be a potential target for MDS patients who developed resistance to BTZ. Our findings are in line with previous report that ERK inhibitors synergized with BTZ on anticancer effects in medulloblastoma cells. Using the MUTZ-1 cell line, Huang et al found no notable changes in p-ERK1/2 after BTZ treatment. The difference in p-ERK expression in response to BTZ treatment may be explained by the nature of the two different cell lines. MUTZ-1 was isolated from the malignant cells of a 5-year-old girl with MDS, whereas SKM-1 was established from leukemic cells of a 76year-old patient. These two cell lines exhibit different chromosome abnormalities. Autophagy is a mechanism that degrades dysfunctional cellular components through lysosomes. The activation of autophagy may lead to either cell death or increased survival depending on cell types and conditions. For example, BTZ-induced autophagy led to cell death in MDS/AML cells. Consistent with these previous findings, our present study showed that BTZ induced the conversion of LC3I to LC3II in wild type SKM-1 cells but not in BTZ resistance SKM-1R cells. Our results suggest that autophagic cell death may contribute, at least in part, to BTZinduced cell cycle arrest and apoptosis. In some cases, the LC3-I to LC3-II conversion is necessary but not sufficient to trigger cell autophagy. Further studies are needed to ascertain the role of autophagy in BTZ induced cell death by silencing autophagy related proteins such as ATG5, ATG7 and ATG8 in Skm-1 cells. In conclusion, the present study demonstrates that BTZ induces cell cycle arrest, apoptosis and autophagy in SKM-1 cells. The cytotoxic effects of BTZ appeared to depend, at least in part, on the inhibition of the MEK/ERK pathway. The BTZ resistant SKM-1R cells are characterized by upregulation of ERK. Based on the present observations, a combinational therapy of BTZ and MAPK inhibitors may be an effective complement to current therapeutic approaches for MDS. Cyclin-dependent kinase inhibitors negatively regulate the cell cycle, helping to set the threshold for cell cycle entry and promoting exit from cell cycle in response to growth factor withdrawal, inhibitory cytokines, contact inhibition, DNA damage, and senescence. Over-expression of these factors can impose cell cycle arrest in a retinoblastoma protein -dependent manner, while elimination of CDK inhibitors leads to enhanced proliferative responses in many types of tissues and cell types. CDK inhibitors are subdivided into two groups based on functional and structural differences. Three different approaches were considered for the BI-D1870 control of more virulent malarial parasite, Plasmodium falciparum. They are widely exploited development of effective vaccines, vector control and development of new drugs. It is very difficult to develop a vaccine due to their exhibition of their multiple antigenicity. Based on several factors, the vector control shows limited success. On the other hand, there is an increasing resistance of malarial parasites to the existing drug hence, there is an urgent need demand for new antimalarial agents.