| Background: Triptolide, a diterpene triepoxide, is a potent antileukemic agent extracted from the Chinese herb Tripterygium wilfordii. In vivo and in vitro, it blocked proliferation and induced apoptosis of leukemic cells. Phase I and II Clinical studies showed that 75% of patients of acute myelogenous leukemia achieved complete remission with the treatment of this compound. However, its use has been limited by its systemic toxicities, i.e. cardiovascular and hepatic toxicities. Therefore, the combination of low-dose triptolide with other anticancer agents would be advantageous to maximize the therapeutic effect and minimize any adverse effect of the drug. Chemotherapy is a common treatment for leukemia and drug resistance is a major factor in chemotherapeutic failure. Multi-drug resistance (MDR) mediated by the over-expression of drug efflux protein P-glycoprotein (P-gp) and MDR protein (MRP) is one of obstacles to successful chemotherapy. Triptolide was established to induce apoptosis of leukemia cells at a low concentration. To explore the effects of triptolide on the P-gp and MRP expressions of MDR leukemia cells will be helpful to evaluate the potential of the agent for the treatment of MDR leukemia.The molecular mechanisms underlying triptolide induced apoptosis in leukemia cells remain poorly understood. Bcl-2 family and p53 are important regulators of apoptosis. It can be speculated that some of them may be involved in the triplide-induced apoptosis. Bcl-2 gene is a critical regulator of the cell death process, which encodes a Bcl-2 protein that promotes cell survival by blocking apoptosis. Bcl-2 can also be converted to a Bax-like death effector. Bax is a pro-apoptotic Bcl-2 family member that binds to the anti-apoptotic Bcl-2 protein, and can antagonize its function to block apoptosis. The cellular wild-type p53 gene is a tumor suppressor gene. It regulates the cell cycle of DNA repair and synthesis, and also programs cell death. During apoptosis, a complex set of proteins is activated. Among them, Caspases play a key role and act as initiators. These cysteine proteases are normally present as pro-enzymes and are proteolytically cleaved to active heterodimers. They have an active-site cysteine and mediate apoptosis by proteolysis of specific substrates. Bcl-2 are known substrates of Caspase-3. Chemotherapeutic agents induce alterations in intracellular signal transduction cascades that culminate in the initiation of the apoptotic program. MAP kinase families are considered as important mediators of apoptotic signals in many cellular systems. The mitogen-induced ERK MAPKs were linked to cell proliferation and survival, whereas the stress-activated MAPKs, p38 and JNK, were connected with apoptosis. All drugs activated MAPKs, but the extent and kinetics of activation were different. In this study, the involvement of RAS-MAPK signal transduction cascades in triptolide treated leukemia cells was investigated.Leukemia is a genomic functional disease with features of oncogene activation and tumor suppressor inactivation. These genomic features have resulted in the limited effectiveness of conventional therapies and therefore forced considerable efforts to explore new types of anticancer agents. In fact, new types of gene drugs such as antisense oligonucleotides, ribozymes and siRNA duplexes are converging a powerful arm to regulating gene expression in leukemia cells. .RNA interference (RNAi) is a cellular pathway of gene silencing in a sequence-specific manner at the messenger RNA level. The basic mechanism behind RNAi is the breaking of a double-stranded RNA (dsRNA) matching a specific gene sequence into short pieces called short interfering RNA (siRNA), which trigger the degradation of mRNA that matches its sequence. SiRNA-induced gene silencing in mammalian cells shows great promise as a tool to reduce the expression of specific genes. It provides new approaches for research and gene therapy. RNAi has many similarities to another RNA regulatory mechanism - ie, antisense. Both act post-trans...
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