Modulation of doxorubicin sensitivity by a novel organic compound, oxalyl bis ( N-phenyl) hydroxamic acid on acetyl aminofluorene-induced preneoplastic hepatocytes

• Published in: Cancer letters Vol. 202; no. 1; pp. 25 - 34
• Main Authors: Choudhuri, S.K, Majumder, Surajit
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 08-12-2003; Elsevier; Elsevier Limited
• Subjects: 2-Acetylaminofluorene - toxicity; Acids; Animals; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Benzeneacetamides - therapeutic use; Biological and medical sciences; Bone marrow; Calcium Channel Blockers - pharmacology; Carcinogens; Carcinogens - toxicity; Cell Division - drug effects; Dose-Response Relationship, Drug; Doxorubicin (Dox); Doxorubicin - therapeutic use; Drug dosages; Drug Synergism; Drug Therapy, Combination; Experiments; Glutathione - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Hydroxamic Acids - therapeutic use; Male; Medical sciences; Methods; Mice; Modulators; Oxalates - therapeutic use; Oxalyl bis ( N-phenyl) hydroxamic acid (OBPHA); Pharmacology. Drug treatments; Precancerous Conditions - chemically induced; Precancerous Conditions - drug therapy; Precancerous Conditions - metabolism; Rats; Rats, Sprague-Dawley; Rodents; Sensitivity; Spleen - metabolism; Survival Rate; Tumor Cells, Cultured; Tumors; Verapamil - pharmacology; GSH, reduced glutathione; P-gp, P-glycoprotein; Doxorubicin (Dox); BSO, buthionine sulphoxamine; OBPHA, oxalyl bis ( N-phenyl) hydroxamic acid; EA, ethacrynic acid; NBT-BCIP, nitro blue tetrazolium chloride and 5-bromo- 4-chloro-3-indolylphosphate-p-toluidine salt; TBST, tris-buffered–saline-tween; Modulators; EAC, Ehrlich ascites carcinoma; Sensitivity; MTT, 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide; ABTS, [2,2′ azino bis (3-ethyl benzthiazoline-6-sulfonic acid)]; SBPHA, succinyl bis ( N-phenyl) hydroxamic acid; Oxalyl bis ( N-phenyl) hydroxamic acid (OBPHA); HEPES, ( N-[2-hydroxy ethyl piperazine- N′[2-ethane sulfonic acid)]; PEN–STREP, Penicillin–streptomycin; DNA topoisomerase (ATP-hydrolysing); Modulator; Digestive system; Enzyme; Liver; Hydroxamic acid; Enzyme inhibitor; Doxorubicin; Isomerases; Hepatocyte; Modulation; Anthracyclins; Oxalyl bis (N-phenyl) hydroxamic acid (OBPHA); Organic compounds
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(03)00474-9

Development of biochemical modulators and application of the same with anticancer drugs is a current approach of modern cancer chemotherapy. We report the effect of two novel hydroxamic acid derivatives, viz. oxaly bis (
N-phenyl) hydroxamic acid (OBPHA) and succinyl bis (
N-phenyl) hydroxamic acid (SBPHA) on doxorubicin sensitivity and on P-glycoprotein (P-gp) in acetyl amino fluorene (AAF) induced preneoplastic hepatocytes in vitro. OBPHA increases doxorubicin sensitivity in AAF induced preneoplastic hepatocytes compared to normal hepatocytes. SBPHA, with an additional –CH
2–CH
2– group than OBPHA does not modulate the sensitivity of doxorubicin. The mechanism of action of OBPHA and SBPHA and their in vivo toxicity on male Swiss mice has been studied. OBPHA in combination with doxorubicin (i.e. OBPHA+doxorubicin) has higher antitumour activity compared to doxorubicin alone group; in consequence, OBPHA may decrease the dose related side effect of doxorubicin.