Molecular signals in anti-apoptotic survival pathways

Abstract

Drug resistance, to date, has primarily been attributed to increased drug export or detoxification mechanisms. Despite correlations between drug export and drug resistance, it is increasingly apparent that such mechanisms cannot fully account for chemoresistance in neoplasia. It is now widely accepted that chemotherapeutic drugs kill tumour cells by inducing apoptosis, a genetically regulated cell death programme. Evidence is emerging that the exploitation of survival pathways, which may have contributed to disease development in the first instance, may also be important in the development of the chemoresistance. This review discusses the components of and associations between multiple signalling cascades and their possible contribution to the development of neoplasia and the chemoresistant phenotype. Leukemia (2001) 15, 21-34.

The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells

“…22-24 GTP-bound Ras subsequently activates downstream signaling proteins, which regulate growth and survival. [3][4][5][6][7] Activating Ras mutations are described in 39% of newly diagnosed myeloma patients 50 and in 64-70% of patients with terminal disease. 24,51,52 The presence of Ras mutations at diagnosis is also associated with a poor response to chemotherapy 51 and a shorter survival.…”

“…Isoprenylation is essential for membrane attachment 2 and participation of the modified proteins in signal transduction processes. [3][4][5][6][7] Lovastatin is a nonreversible competitive inhibitor of HMGCoA reductase and is widely used for the treatment of hypercholesterolemia. 8 Lovastatin blocks the enzymatic conversion of HMG-CoA to mevalonate and subsequently the synthesis of downstream mevalonate products.…”

A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells

“…6 The development of resistance to a wide spectrum of cytotoxic drugs frequently impedes the successful treatment of acute myeloid leukemia either at the initial presentation or following primary or subsequent relapses. 7 Moreover, ATRA resistance in acute promyelocytic leukemia is rare but markedly increases in frequency after relapses from chemotherapyinduced clinical remission. 8 In some cases, drug and ATRA resistance might be the consequence of failure of leukemic cells to undergo apoptosis.…”

mTOR, A New Therapeutic Target in Acute Myeloid Leukemia

“…[12][13][14] Moreover, these anti-apoptotic signalling pathways are involved in the resistance to cytotoxic agents currently used in the treatment of this disease. 15,16 Although this simplified chain of events does not involve other disease features such as interactions with the microenvironment, angiogenesis, genomic instability or escape from the immune response, it points to crucial pathways that could be used as therapeutic targets. Indeed, small molecule inhibitors of the FLT3 receptor tyrosine kinase (RTK) or RAS are now being evaluated in phase II/III clinical trials in AML.…”