Methods of increasing the cytotoxicity of chemotherapeutic agents with multisubstrate inhibitors of histone, protein-lys, polyamine acetylation, and polyamine metabolism
A method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of a compound of the HAT inhibitor of the following formula: wherein R is chosen from coenzyme A, (CH 2 ) 2 NHCO(CH 2 ) 2 NHCOR 2 ; (CH 2 ) 2 NHCOR 3 ; (CH 2 ) 2 NHCO(CH 2 ) 2 NHCOR 4 ; R 1 is H, NH 2 , NH, N, and R 1 can optionally cyclize with at least one other X 2 to form a C 3-8 membered ring containing C, O, S, or N; R 2 is chosen from alkyl, cycloalkyl, aryl, heteroaryl; R 3 is chosen from an alkyl, cycloalkyl, aryl, heteroaryl; R 4 is chosen from CH(OH)C(CH 3 ) 2 CH 2 )OCOR 2 ; X 1 is chosen from H or can cyclize with one other X 2 or R 1 to form a C 3-8 membered ring containing C, O, S, or N; and X 2 is chosen from C, N, NH, and can optionally cyclize with at least one other X 2 or R 1 to form a C 3-8 membered ring containing C, O, S, or N; or a pharmaceutically acceptable salt or hydrate thereof, thereby treating the cancer.
1. A method of treating cancer in a subject in need thereof, comprising
(i) administering to the subject a therapy sensitizing effective amount of a HAT inhibitor of the following formula:
wherein
R is chosen from coenzyme A, (CH 2 ) 2 NHCO(CH 2 ) 2 NHCOR 2 , (CH 2 ) 2 NHCO(CH 2 ) 2 NHCOR 4 ;
R 2 is methyl;
R 4 is chosen from CH(OH)C(CH 3 ) 2 CH 2 )OCOR 2 ;
or a pharmaceutically acceptable salt or hydrate thereof, and
(ii) administering to said subject in need thereof an anti-cancer agent or a therapeutic anti-cancer agent combination; thereby treating the cancer.
2. The method of claim 1 , wherein the HAT inhibitor is a composition that comprises a compound of the following formula:
wherein R is (CH 2 ) 2 NH—CO—(CH 2 ) 2 NH—CO—CH 3 .
3. The method of claim 1 , wherein the cancer comprises an inherent defect in DNA repair.
4. The method of claim 3 , wherein the cancer has a defect in BrCA 1.
5. The method of claim 3 , wherein the cancer has a defect in BraCa2.
6. The method of claim 3 , wherein the cancer is breast cancer.
7. The method of claim 1 , wherein the anticancer agent is chosen from carboplatin, gemcitabine, cisplatin, 5-fluorouracil, cyclophosphamide, etoposide, vincristine, doxorubicin, DFMO and/or irinotecan.