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Lysosomal Acidification Defect A Plausible Mechanism of Cisplatin

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Lysosomal Acidification Defect A Plausible Mechanism of Cisplatin Powered By Docstoc
					INDIAN JOURNAL OF MEDICAL & PAEDIATRIC ONCOLOGY            Vol. 27 Suppl. 1, 2007               19




               Lysosomal Acidification Defect: A Plausible
                  Mechanism of Cisplatin Resistance
                                    Shyam S. Chauhan
                                 Department of Biochemistry
                            All India Institute of Medical Sciences,
                                Ansari Nagar, New Delhi-110029


Cisplatin (CP) is a component of standard            after uptake into lysosmes of KB-CP-r cells
treatment regimens for ovarian, cervical,            was TCA precipitable as compared to only
testicular, bladder, head and neck and lung          10% released by sensitive cells. These results
cancer. Adduct of DNA with CP induce                 indicate inefficient degradation of
apoptosis leading to cell death. Intrinsic or        internalised 125I-EGF in the lysosomes of KB-
acquired resistance of tumourous cells to CP         CP-r cells, consistent with slower
under mines its clinical effectiveness. In           processing of cathepsin L, a lysosomal
order to understand the molecular basis CP           cysteine protease. Treatment of KB cells by
resistance we isolated human KB                      bafilomycin A 1, A known inhibitor of the
adenocarcinoma cisplatin-resistant (CP-r)            vacuolar proton pump, mimicked the
cell lines with multidrug-resistance                 phenotype seen in KB-CP-r cells with
phenotypes        because      of    reduced         reduced uptake of HRPO, 125 I-EGF, 14 C-
accumulation of CP and other cytotoxic               carboplatin and release of TCA precipitable
compounds such as methotrexate and heavy             125I-EGF. KB-CP-r cells also had less acidic
metals. The uptake of horseradish                    lysosomes. KB-CP-r cells were crossresistant
peroxidase (HRPO) and Texas Red dextran              to Pseudomonas exotoxin, and Pseudomonas
was decreased several-fold in KB-CP-r cells,         exotoxin-resistant       KB     cells    were
indicating a general defect in fluid phase           crossresistant to CP. Since cells with
endocytosis. In contrast, although EGF               endosomal acidification defects are known to
receptors were decreased in amount the               be resistant to Pseudomonas exotoxin and
kinetics of EGF uptake, a marker of                  blocking of endosomal acidification mimics
receptormediated endocytosis, was similar            the CP-r phenotype, we conclude that
in sensitive and resistant cells. However, 40-       defective endosomal acidification may
60% of the 125I-EGF released into the medium         contribute to acquired CP resistance.


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