Multidrug transporter proteins and cellular factors involved in free and mAb linked calicheamicin-gamma1 (gentuzumab ozogamicin, GO) resistance and in the selection of GO resistant variants of the HL60 AML cell line.
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.
Cianfriglia
Maurizio
M
Section of Pharmacogenetics, Drug Resistance and Experimental Therapeutics, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy. maurizio.cianfriglia@iss.it
Mallano
Alessandra
A
Ascione
Alessandro
A
Dupuis
Maria Luisa
ML
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D000617:Aminoglycosides / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D053281:Enediynes / Q000494:pharmacology*; D000079982:Gemtuzumab; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics*; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D053281:Enediynes; D000079982:Gemtuzumab; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D063268:Sialic Acid Binding Ig-like Lectin 3; C571163:CD33 protein, human; C055955:calicheamicin gamma(1)I; C421109:multidrug resistance-associated protein 1