Potential of the proteasomal inhibitor MG-132 as an anticancer agent, alone and in combination.
Proteasomal activity is required for normal cellular functions including cell division, where entry and exit from mitosis is strictly regulated by cyclins and cyclin-dependent kinases which are among the important substrates of the proteasomal degradative machinery. Inhibitors of proteasomal activity have been shown to be effective inducers of apoptosis in tumor cells and may be useful as anticancer agents, either alone or in combination with other drugs. We have examined the effect of MG-132, a dipeptide proteasomal inhibitor, on various human cancer cell lines. We have also examined the effect of MG-132 on normal CD34+ enriched primary human peripheral blood stem cells. Our results indicate that MG-312 is a potent anticancer agent with cytotoxic effects on a variety of human cancer cell lines irrespective of their p53 status. MG-132 was found to be more effective in combination with drugs such as doxorubicin and etoposide that act in the S/G2-phase of the cell cycle via a mechanism that involves stabilization of cyclin B1 and increased expression of Bax. Further, MG-132 inhibits CFU-GM colony formation of the CD34+ enriched PBSC population and this inhibition correlates with release of cyt C into the cytosol.
Banerjee
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D
Sloan Kettering Institute for Cancer Research, Molecular Pharmacology and Experimental Therapeutics Program, New York, NY 10021, USA. banerjed@mskcc.org
Liefshitz
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A
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage; D016193:G1 Phase / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020014:K562 Cells / Q000166:cytology / Q000187:drug effects; D007976:Leupeptins / Q000008:administration & dosage / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D046988:Proteasome Endopeptidase Complex; D016196:S Phase / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde