Role of the lung resistance-related protein (LRP) in the drug sensitivity of cultured tumor cells

• Published in: Toxicology in vitro Vol. 16; no. 4; pp. 389 - 398
• Main Authors: Meschini, S., Marra, M., Calcabrini, A., Monti, E., Gariboldi, M., Dolfini, E., Arancia, G.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Oxford Elsevier Ltd 01-08-2002; Elsevier Science
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; Biological and medical sciences; Breast Neoplasms - pathology; Carcinoma, Non-Small-Cell Lung - pathology; Chemotherapy; Confocal microscopy; Cultured tumor cells; Cytoplasm - chemistry; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - physiology; Drug sensitivity; Female; Flow Cytometry; Humans; LRP; Lung Neoplasms; Medical sciences; Multidrug Resistance-Associated Proteins - biosynthesis; Neoplasm Proteins - metabolism; Neoplasm Proteins - pharmacology; Pharmacology. Drug treatments; Transport proteins; Tumor Cells, Cultured; Vault Ribonucleoprotein Particles - metabolism; PBS; Flow cytometry; P-gp; NSCLC; MVP; Confocal microscopy; Cultured tumor cells; MRP; LRP; MFC; DOX; BSA; FCS; Transport proteins; MDR; SEM; HBSS; SCLCs; Drug sensitivity; Antineoplastic agent; Human; Cell culture; Treatment resistance; Lung; Biological marker; Doxorubicin; In vitro; Chemotherapy; Cell line; Anthracyclins; Mammary gland; Intracellular; Mechanism of action; Tumor cell; Carrier protein
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/S0887-2333(02)00035-8

Drug resistance, one of the major obstacle in the successful anticancer therapy, can be observed at the outset of therapy (intrinsic resistance) or after exposure to the antitumor agent (acquired resistance). To gain a better insight into the mechanisms of intrinsic resistance we have analyzed two human cell types derived from untreated tumors: MCF-7 breast cancer and A549 non small cell lung cancer (NSCLC). We have examined: the cytotoxic effect induced by doxorubicin (DOX); the time course of drug accumulation by flow cytometry and intracellular drug distribution by confocal microscopy; the expression and distribution of proteins related to anthracycline resistance, such as P-gp (P-glycoprotein), MRP1 (multidrug resistance-associated protein) and LRP (lung resistance-related protein). The cytotoxicity assays showed that A549 cells were less sensitive than MCF-7 cells to the DOX treatment in agreement with the different DOX uptake. Moreover, while in A549 cells DOX was mostly located in well defined intracytoplasmic vesicles, in MCF-7 cells it was mainly revealed inside the nuclei. The analysis of P-gp and MRP expression did not show significant differences between the two cell lines while a high expression of LRP was detected at the nuclear envelope and cytoplasmic levels in A549 cells. These findings suggest that the lower sensitivity to DOX treatment showed by lung carcinoma cells could be ascribed to drug sequestration by LRP inside the cytoplasmic compartments.