Cell signalling in survival: Natural compounds and small-molecule inhibitors provide essential insight

Effective response to treatment is still a challenge in the clinical management of many types of tumors. As result of pharmacological intervention two different fates are observed for a cancer cell: survival or death. These two cell fates are intimately related to the overall response to treatment. Survival of a cancer cell to an aggressive treatment usually means inefficacy of a determined drug and cell death means that the cells were sensitive to the treatment. In the current literature many types of cell death are suggested. Of equal importance is the understanding of the mechanisms and signal cascades of survival. Crosstalk between multiple signal transduction pathways may organize an intricate survival network with overlapping functions that together provide strong survival signals to a dying cell. Importantly, these survival signals seem to be on the background of the classic mechanism of drug resistance which holds true for a lower efficacy of determined class of molecules or structurally unrelated ones, such as drug efflux, drug uptake, drug metabolism, DNA repair and impaired drug binding to its target. Importantly, different types of tumors present different aspects of surviving, as an example the building up of a drug resistant phenotype in hematological diseases is usually a long term process, resulting in an initial response to treatment. However, relapses occur after sometime, and not always remission is achieved with the same therapeutic strategy. The development or acquisition of drug resistance is a quite remarkable aspect of hematological malignancies. On another hand, this first response to pharmacological strategies is not really achieved in tumors such as, pancreatic cancer (PDAC). Less than 10% of patients treated with gemcitabine (first line of treatment for PDAC) present an objective response to this treatment. Many aspects of PDAC, such as poor vascularization, fibrosis and the upregulation of many important survival signal transduction pathways in these tumors, favor a development of an intrinsically resistant phenotype.

• View at Worldcat

Free Full Text ( Final Version , 15mb )