Altered expression of P‐glycoprotein and cellular adhesion molecules on human multi‐drug‐resistant tumor cells does not affect their susceptibility to NK‐ and LAK‐mediated cytotoxicity

Abstract

Drug resistance has been associated with resistance to NK- and LAK-cell-mediated cytotoxicity. We evaluated this issue in human cell lines, using multiple myeloma cells (8226) and 2 multi-drug-resistant (MDR) sublines selected using doxorubicin (8226/Dox40) and mitoxantrone (8226/MR40). In parallel, we studied the human breast carcinoma cell line series MCF7, MCF7/D40 and MCF7/Mitox. Unlike the sensitive parental cell lines, all 4 sublines display MDR-patterns of resistance, with the P-glycoprotein pump (P-170) detected only in the doxorubicin-selected sublines. Flow cytometric and immunocytochemical analyses showed expression of cellular adhesion molecules ICAM-I and LFA-3, and MHC-Class-I (MCF7/D40 only), to be decreased in the doxorubicin-selected MDR-sublines, whereas expression of CD56 (Leu 19) was strongly up-regulated in 8226/Dox40. Lysis of P-170-positive MDR tumor cells by NK or LAK cells was, however, unaffected by these alterations, suggesting redundancy in effector:target-cell adhesion pathways. Mitoxantrone-selected tumor cells did not display P-170, nor did they show altered expression of cellular adhesion molecules. Their susceptibility to NK or LAK cytolysis was also unimpaired as compared to the parental cell lines. Clinically, these results imply that immunotherapeutic modalities aiming at increased natural killer functions deserve full consideration even in patients who have become refractory to further cytostatic drug treatment.

Vaults Are Up-regulated in Multidrug-resistant Cancer Cell Lines

“…As summarized in Table II, vault levels per cell vary considerably among the different cell lines examined and, consistent with our hypothesis, lines with lower levels of endogenous vault particles (GLC4/S and MCF7/S) showed the highest fold induction seen in Table I. Among the lines described in Table II, two (GLC4 and SW1573) were selected with doxorubicin (18 -21), the others were selected with mitoxanthrone (21,22). The very high number of vaults in the GLC4 drug resistant line (245,000 vaults per cell) might reflect the high concentration of doxorubicin to which this line is resistant (1 M), this level of doxorubicin is ten times greater that the level used to select the SW1573 resistant lines 0.1 M (6) which display only one third the number of vaults per cell.…”

Evidence for the involvement of ecto-5′-nucleotidase (CD73) in drug resistance

“…MDR cells may also ovcr-express kinases (Sampson et al, 1993), especially protein kinase C (Posada et al, 1989), as well as other enzymes: e.g., myeloperoxidase (Schlaifer et al, 1993), transglutaminase (Mehta, 1994) and alkaline phosphatase (Uhrik et al, 1994). In some MDR cell lines the cxpression of leukocyte differentiation antigens CD34 (Minderman et al, 1994), CD36 (Sugimoto et al, 1993) and CD56 (Scheper et al, 1991) has been shown to be up-regulated. Finally, epidermal growth factor receptor (Diekstein et al, 1993) and tubulins (Houghton et al, 1985) have also been found to be overexpressed in MDR cells.…”

Natural killer cell immunotherapy against multiple myeloma: Progress and possibilities

“…) . It is worth mentioning that the activation of NK cell‐based immunotherapy against myeloma cells still deserves application even if patients have drug resistance …”

“…The capacity depends on the combined effect of suppressive and stimulatory signals delivered through surface receptors. The novel drugs, including mAbs, PIs, and IMiDs, through their responding receptors or ligands activate NK cells, in order to achieve the purpose of antitumor mentioning that the activation of NK cell-based immunotherapy against myeloma cells still deserves application even if patients have drug resistance 47.…”