Overcoming drug resistance by enhancing apoptosis of tumor cells.
Drug resistance remains a major clinical challenge for cancer treatment. One mechanism by which tumor cells develop resistance to cytotoxic agents and radiation is related to resistance to apoptosis. Apoptosis is a well-organised process of cell death pre-programmed inside the cell. Apoptosis can be initiated either by activation of death receptors on the cell surface membranes (extrinsic pathway) or through a series of cellular events primarily processed at mitochondria (intrinsic pathway). Apoptosis has been shown to be important for tumorigenesis and cancer treatment. Defects in apoptosis can result in the expansion of a population of neoplastic cells. However, because the death of tumor cells induced by chemotherapy and radiotherapy is largely mediated by activation of apoptosis, inhibition of apoptosis will make tumor cells resistant to anti-tumor treatment. Herein, we will review the molecular changes that have the potential to cause apoptotic dysregulation, including activation of antiapoptotic factors (Bcl-2, BCLX(L), Bfl1/A1 etc.), inactivation of pro-apoptotic effectors (p53, p53 pathway), and /or reinforcement of survival signals (Survivin, FLIP, NF-kappaB etc). Furthermore, we will discuss therapeutic intervention and/or strategies that can lower the threshold for apoptosis of tumor cells that could became useful approaches to treat cancer with special emphasis placed on the important priority to develop new cancer therapeutics toward tumor stem cells.
Departament de Ciències Fisiològiques II, Campus Ciènces de Salut de Bellvitge, IDIBELL, University of Barcelona, Barcelona, Spain.
Pepita
P
Giménez-Bonafé
Avelina
A
Tortosa
Ricardo
R
Pérez-Tomás
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D054353:Perforin / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D053218:Receptors, Death Domain / Q000187:drug effects / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D054353:Perforin