This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Warren, L. Articles by Ordentlich, P. Search for Related Content PubMed PubMed Citation Articles by Warren, L. Articles by Ordentlich, P.

Secretion of Lysosomal Enzymes by Drug-sensitive and Multiple Drug-resistant Cells¹

Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104

The multiple drug-resistant human lymphoblastic leukemic cell, CEM/VLB₁₀₀, in which P-glycoprotein (P-170) is overexpressed, has a lowered content of lysosomal enzymes, such as N-acetylglucosaminidase and ß-galactosidase, and the relative rates of secretion of these enzymes are significantly greater than those of its drug-sensitive counterpart, CEM. The ability of CEM/VLB₁₀₀ cells to accumulate [³H]vinblastine ([³H]VLB) is also greatly reduced. Multiple drug-resistant cells whose mode of resistance is not associated with P-170 do not have reduced enzyme content, and their rate of secretion is the same as that of their drug-sensitive parents. Linkage of drug and enzyme elimination is suggested by the observation that verapamil inhibits both the efflux of [³H]VLB and the secretion of lysosomal enzymes in CEM/VLB₁₀₀ cells; the content of both [³H]VLB and enzyme increases in these cells when chronically exposed to verapamil. Further, both secretion of N-acetylglucosaminidase and efflux of [³H]VLB by CEM/VLB₁₀₀ cells are enhanced by the addition of NaCl to the suspending, sucrose-containing medium.

When cells have taken up [³H]VLB and are then fractionated by means of a Percoll centrifugation gradient, the distribution of drug among the various populations of vesicles is similar to that of N-acetylglucosaminidase. Losses of both enzyme and drug take place from these vesicular populations to varying degrees, when CEM/VLB₁₀₀ cells are induced to secrete.

It is proposed that, in a multiple drug-resistant cell such as CEM/VLB₁₀₀, the presence of P-170 in the plasma membrane may, in some indirect manner, lead to increased exocytosis of lysosomal enzyme, ultimately resulting in a significant depletion of enzyme. Further, a toxic, cationic drug such as vinblastine, accumulating in lysosomes and acidic vesicles, is also eliminated from the cell by exocytosis. This pathway may supplement the known, major mode of efflux directly involving P-170.

¹ This work was supported by Grants CA-19130 and CA 10815 from the USPHS and by the American Cancer Society (Grant RDP-19H).

² To whom requests for reprints should be addressed.

³ On sabbatical leave from Groupe d'Etude des Interactions Biologique des Substances Anticancereuses (G. I. B. S. A.), Institut Jean Godinot, and UER Pharmacie, University of Reims, Reims, France.

Received 4/ 9/90. Accepted 1/31/91.

This article has been cited by other articles:

				P. K. Selbo, A. Weyergang, A. Bonsted, S. G. Bown, and K. Berg Photochemical Internalization of Therapeutic Macromolecular Agents: A Novel Strategy to Kill Multidrug-Resistant Cancer Cells J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 604 - 612. [Abstract] [Full Text] [PDF]

				R. Safaei, B. J. Larson, T. C. Cheng, M. A. Gibson, S. Otani, W. Naerdemann, and S. B. Howell Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells Mol. Cancer Ther., October 1, 2005; 4(10): 1595 - 1604. [Abstract] [Full Text] [PDF]

				G. Jansen, H. Barr, I. Kathmann, M. A. Bunni, D. G. Priest, P. Noordhuis, G. J. Peters, and Y. G. Assaraf Multiple Mechanisms of Resistance to Polyglutamatable and Lipophilic Antifolates in Mammalian Cells: Role of Increased Folylpolyglutamylation, Expanded Folate Pools, and Intralysosomal Drug Sequestration Mol. Pharmacol., April 1, 1999; 55(4): 761 - 769. [Abstract] [Full Text]

				C. Millot, J.-M. Millot, H. Morjani, A. Desplaces, and M. Manfait Characterization of Acidic Vesicles in Multidrug-resistant and Sensitive Cancer Cells by Acridine Orange Staining and Confocal Microspectrofluorometry J. Histochem. Cytochem., September 1, 1997; 45(9): 1255 - 1264. [Abstract] [Full Text] [PDF]