Abstract
In this study we elucidated the role of ATP-binding cassette (ABC) multi-drug transporter proteins and cellular factors such as Bcl-2 expression and CD33 down-modulation contributing to free and hP67.6 mAb linked calicheamicin-gamma1 (CalC-gamma1) resistance. We analyzed in a well designed HL60 cell system the relationship between the expression of ABC proteins, Bcl-2 and CD33 modulation with the activity of free and mAb-linked CalC-gamma1. The results herein reported and discussed, strongly suggest that both MDR1-Pgp and MRP1 efflux systems are engaged by CalC-gamma1, but only MDR1-Pgp over-expression efficiently abrogates drug cytotoxicity in MDR cells. Paradoxically, Bcl-2 expression, as observed for other anticancer compounds belonging to the enediyne family of drugs, confers CalC-gamma1 susceptibility rather than resistance in HL60 cells. Further, the isolation of a resistant HL60 subline (HL60AL) that was developed by exposing the parental sensitive cells to sub-effective doses of gemtuzumab ozogamicin (GO) over an extended period of time shows a reduced level of CD33 expression that represents an important escape mechanism of HL60 MDR cells to the cytotoxic effect of GO.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
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Aminoglycosides / pharmacology*
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Antibiotics, Antineoplastic / pharmacology*
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal, Humanized
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Antigens, Differentiation, Myelomonocytic / genetics
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Antigens, Differentiation, Myelomonocytic / metabolism
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Apoptosis / drug effects
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm / genetics*
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Enediynes / pharmacology*
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Gemtuzumab
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Humans
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Multidrug Resistance-Associated Proteins / biosynthesis
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Multidrug Resistance-Associated Proteins / genetics*
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Phenotype
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Sialic Acid Binding Ig-like Lectin 3
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Aminoglycosides
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Antibiotics, Antineoplastic
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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CD33 protein, human
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Enediynes
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Multidrug Resistance-Associated Proteins
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Proto-Oncogene Proteins c-bcl-2
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Sialic Acid Binding Ig-like Lectin 3
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calicheamicin gamma(1)I
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Gemtuzumab
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multidrug resistance-associated protein 1