Deactivation of P-glycoprotein by a novel compound, oxalyl bis (N-phenyl) hydroxamic acid.
A plasma membrane glycoprotein (P-gp) of 170 kd is over-expressed in most of the drug resistant cells. P-gp is encoded in humans by the gene mdrl and is thought to function as a broad substrate ATP-dependent drug efflux pump. P-gp is also present in many types of normal cells. A good number of chemicals inhibit or deactivate P-gp and thus reverse multidrug resistance (MDR). Most of the reported resistance modifying agents (RMAs) are effective in vitro and have adverse effect on the hosts. Hence, the development of nontoxic RMA is of immense importance in the field of cancer chemotherapy. With this end in view, a nontoxic resistance modifying agent, viz., oxalyl bis (N-phenyl) hydroxamic acid (OPHA) has been developed on the basis of the structural commonalities of the reported RMAs. We reported earlier that OPHA reverses doxorubicin resistance in vitro and also reduces glutathione and glutathione S-transferase in a non P-gp expressing cell line. In the present report, the inhibition of P-gp by the compound, OPHA in human cervical cancer cell line, HeLa, has been described by western blotting, study of immunofluorescence and enzyme linked immunofluorescence assay (ELISA). The inhibition of P-gp by OPHA is significantly higher than that of verapamil. The high IC50 values of OPHA against different cell lines indicate the non toxic nature of the compound. This work underscores the possibility of using the present hydroxamic acid derivative as the nontoxic modulator of the MDR phenotype.
Choudhuri
S K
SK
Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, Calcutta- 700 026 India. soumitra01@vsnl.net
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D044482:Benzeneacetamides; D015153:Blotting, Western; D002460:Cell Line; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010070:Oxalates / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044482:Benzeneacetamides; D006877:Hydroxamic Acids; D010070:Oxalates; C117053:oxalyl bis(N-phenyl)hydroxamic acid; D014700:Verapamil