Therapeutic advantage of combining calcium channel blockers and TRAIL in prostate cancer
| Autor: | Ismail Kaddour-Djebbar, M. Vijay Kumar, Robert B. Shirley, Vijayabaskar Lakshmikanthan, Ronald W. Lewis, Yulin Ma |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Thiazepines chemistry.chemical_element Apoptosis Mitochondrion Calcium Biology Calcium in biology Clonazepam Sodium-Calcium Exchanger TNF-Related Apoptosis-Inducing Ligand Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Tumor Cells Cultured Humans Uniporter Calcium channel Prostatic Neoplasms Drug Synergism Calcium Channel Blockers Molecular biology Mitochondria Endocrinology Oncology chemistry Cancer cell Androgens Tumor necrosis factor alpha |
| Zdroj: | Molecular cancer therapeutics. 5(8) |
| ISSN: | 1535-7163 |
| Popis: | Disruption of intracellular calcium initiates multiple cell-damaging processes, such as apoptosis. In normal cells, the levels of Ca2+ are low in the mitochondria, whereas in apoptotic cells, Ca2+ increases. Mitochondria uptake Ca2+ via an inner membrane channel called the uniporter and extrude it into the cytoplasm through a Na+/Ca2+ exchanger. Overload of Ca2+ in the mitochondria in CGP-treated cells leads to its damage, thus affecting cellular function and survival. The goal of these experiments was to determine the importance of mitochondrial calcium ([Ca2+]m) in apoptosis of prostate cancer cells. Furthermore, we have examined the advantages of increasing the [Ca2+]m and treating the cells with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a potent apoptotic agent. Our results show that, under these treatment conditions, inhibiting the Na+/Ca2+ exchanger using benzothiazepin CGP-37157 (CGP) did not induce apoptosis. However, combination of CGP and TRAIL increased the apoptotic response ∼25-fold compared with control. Increase in apoptosis followed enhanced levels of [Ca2+]m and was accompanied by pronounced mitochondrial changes characteristic of mitochondria-mediated apoptosis. Experiments with calcium ionophores showed that mere increase in cytosolic and/or mitochondrial Ca2+ was not sufficient to induce apoptosis. These results have therapeutic implications as inhibitors of Na+/Ca2+ exchanger are being used for treating some neurologic and cardiologic ailments, and TRAIL induces apoptosis preferentially in cancer cells. Furthermore, this system provides an excellent model to investigate the role of [Ca2+]m in apoptosis. [Mol Cancer Ther 2006;5(8):1958–66] |
| Databáze: | OpenAIRE |
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