April 21, 2005
Selenium will have critical role in prostate cancer treatment - Fox Chase Cancer CenterTopics: Nutrition and Cancer
[TRAIL - tumor necrosis factor-related apoptosis-inducing ligand.]
One of the more interesting facets of the topic of this article addressing selinium-facilitated TRAIL-induced apoptosis is that it touches upon the important consideration of tumor micro-environment.
Researchers at Fox Chase Cancer Center in Philadelphia have come a step closer to understanding selenium's molecular role in causing prostate cancer cells to self-destruct. According to data presented today at the 96th Annual Meeting of the American Association for Cancer Research in Anaheim, Calif., selenium helps malignant cells overcome their resistance to TRAIL-induced apopstosis (self-inflicted cell death). Previous studies had shown that TRAIL, a cytotoxic agent being investigated as a new therapeutic agent for cancer, causes malignant cells to self-destruct. Yet some cells resist the treatment.For cells that resist treatment, agents that sensitize malignant cells to TRAIL-mediated cell death might be of particular importance for the development of novel anti-tumor therapeutic regimens. The researchers believe that selenium could be an agent that will sensitize the malignant cells to a TRAIL-induced death.
"Selenium and vitamin E are the most promising dietary supplements considered for use in the reduction of prostate cancer risk," Kolenko said. "This enthusiasm is reflected in the initiation of the large National Cancer Institute sponsored trial - SELECT (Selenium and Vitamin E Chemoprevention Trial). The epidemiologic studies within SELECT will be based on 32,000 men."
With this in mind, Kolenko and colleagues went a step further and studied the effect of methylseleninic acid (MSA), a novel selenium metabolite, in inducing apoptosis in different types of prostate cancer cells (androgen-dependent LNCaP and androgen-independent, PC-3 and DU-145).
"The cytotoxic effect of TRAIL in combination with MSA in LNCaP and DU-145 cells was evaluated using a DNA fragmentation assay," Kolenko explained. "Treatment of prostate cancer cells with TRAIL alone for 24 hours induced negligible levels of apoptosis. Treatment with MSA alone also failed to induce a significant level of cell death in LNCaP cells, although it induced notable apoptosis in DU-145. However, concomitant treatment with TRAIL and MSA resulted in profound DNA fragmentation in both LNCaP and DU-145 cells" (74.3% and 61.5% correspondingly).
"Taken together our data reveal a potential mechanism for the synergistic effect of TRAIL and MSA on the induction of apoptosis in prostate cancer cells," Kolenko concluded. "The combination of TRAIL and MSA may be a novel strategy for the development of innovative therapeutic modalities targeting apoptosis-resistant forms of prostate cancer."
Tumor microenvironment, which is characterized by hypoxia, low-glucose concentrations, high-lactate concentrations, low-extracellular pH, can alter the therapeutic response in tumors. Research suggests that hypoxia or low glucose-augmented TRAIL cytotoxicity is mediated through the mitochondria-independent pathway or -dependent pathway, respectively.
Methylseleninic acid potentiates apoptosis induced by chemotherapeutic drugs in androgen-independent prostate cancer cells.
Redox modulation of human prostate carcinoma cells by selenite increases radiation-induced cell killing.
Enhanced induction of apoptosis by combined treatment of human carcinoma cells with X rays and death receptor agonists.
TRAIL sensitizes for ionizing irradiation-induced apoptosis through an entirely Bax-dependent mitochondrial cell death pathway.
Posted by Richard at April 21, 2005 11:08 AM
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