Bcl-2 has differing effects on the sensitivity of breast cancer cells depending on the antineoplastic drug used.
The aim of this paper was to evaluate the role of bcl-2 in the susceptibility of the MCF7 ADR human breast carcinoma line overexpressing the P-170 glycoprotein (P-170) to various drugs. The sensitivity to four multidrug resistance (MDR)-related drugs (doxorubicin (ADR), vincristine (VCR), vinblastine (VBL), actinomycin D (ACTD)) and three MDR-non-related drugs (cisplatin (DDP), bischloroethylnitrosourea (BCNU), 5-fluorouracil (5-FU)) was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay in three bcl-2-overexpressing clones obtained from the MCF7 ADR line. We found that the bcl-2-overexpressing clones show increased resistance to DDP and BCNU, while no difference to 5-FU were observed between the control cells and bcl-2 transfectants. Surprisingly, bcl-2-overexpressing clones displayed an increased sensitivity compared with the control cells to the MDR-related drugs ADR, VCR, VBL and ACTD. Focusing on DDP and ADR, we found that the increased resistance of the bcl-2 transfectants to DDP was correlated to their ability to prevent apoptosis, while the enhanced sensitivity to ADR was associated with an increased ADR accumulation and a decreased ADR efflux. Moreover, while bcl-2 overexpression does not induce changes in P-170 glycoprotein expression, it did induce a reduction of the adenosine triphosphate (ATP) levels and basal protein kinase C (PKC) activity, both of which have a crucial role in the regulation of the MDR phenotype. In conclusion, the effect of bcl-2 on antineoplastic sensitivity observed in this study underscores the idea that bcl-2 may have distinct biological effects depending on the anticancer drug used.
Del Bufalo
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D
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy.
Biroccio
A
A
Trisciuoglio
D
D
Bruno
T
T
Floridi
A
A
Aquino
A
A
Zupi
G
G
D000255:Adenosine Triphosphate / Q000032:analysis; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D019254:Genes, bcl-2 / Q000502:physiology*; D006801:Humans; D011493:Protein Kinase C / Q000032:analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000255:Adenosine Triphosphate; D011493:Protein Kinase C