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H Garewal

Publications and source records attributed to H Garewal.

42 records · Page 3Linked to original sources
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Mitochondrial perturbation attenuates bile acid-induced cytotoxicity.

Hydrophobic bile acids such as deoxycholate (DOC) are known to damage liver cells during cholestasis and promote colon cancer. Cellular stresses induced by bile acids, which include mitochondrial and endoplasmic reticulum (ER) stresses, can result in apoptosis. We found that inhibition of mitochondrial complexes I-V with rotenone, thenoyltrifluoroacetone (TTFA), antimycin A, myxothiazol or oligomycin strongly protected against DOC-induced apoptosis of HCT-116 cells. To understand the mechanism of this protection, we explored the ability of these specific inhibitors to reduce DOC-induced mitochondrial and ER stresses. Different inhibitors markedly reduced DOC-induction of mitochondrial condensation, the DOC-induced decrease in mitochondrial membrane potential and the DOC-induced dilatation of the ER (evidence of ER stress). A dramatic induction of nucleolar segregation by antimycin A and myxothiazol, two distinct complex III inhibitors, was also observed. These findings strongly implicate mitochondrial crosstalk with apoptotic signaling pathways and mitochondrial-nucleolar crosstalk in the development of apoptosis resistance in the colon.

Antimycin A↗
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Role of apoptosis in biology and pathology: resistance to apoptosis in colon carcinogenesis.

The overview of apoptosis presented here emphasizes cell deletion in the immune system, with particular reference to T- and B-lymphocyte development, and the in vivo and in vitro senescence of human neutrophils. Some biochemical criteria that are used to identify apoptotic cells are described. Pitfalls in using agarose gel electrophoresis as the sole method for the identification of apoptotic cells are discussed. There are multiple modes of cell death that can be identified at the morphologic level. Thus the central role of microscopic methods, and in particular, electron microscopy, as an important tool in the study of cell death mechanisms, is presented. Apoptosis has a protective role against disease and could, a priori, have an important role in either the initiation or progression of cancer. Two paradoxes concerning the relationship of tumor aggressiveness at the clinical level to mitotic activity have been explained by an evaluation of apoptotic index. In the first case, basal cell carcinomas grow slowly but show a high rate of mitosis. Here, the apoptotic rate is quite high, but just below the mitotic rate, thereby accounting for the slow rate of growth. A second instance is follicular lymphoma, which has a low rate of mitosis that is less than that described for reactive germinal centers. However, apoptosis is markedly reduced in follicular lymphomas compared with that seen in reactive germinal centers, thus providing an explanation for the progressive growth of the follicle. We present a brief description of recent work from our laboratory that indicates that apoptosis may play an important role in colon carcinogenesis. We have shown that sodium deoxycholate, the particular bile salt present in highest concentration in the colon, induces apoptosis in the goblet cells of the human colonic mucosa in an in vitro assay. The intriguing finding is that cells of the normal-appearing mucosa of colon cancer patients are resistant to bile salt-induced apoptosis. This suggests a novel hypothesis about the etiologic role of bile salts in colon cancer. The chronic presence of bile salts that accompany a high-fat diet could select for apoptosis-resistant epithelial cells in the colon over time. Thus, a resistance-to-apoptosis bioassay may prove useful as an intermediate biomarker for determining which individuals are at high risk for colon cancer.

Apoptosis↗