Synergistic interactions between aminoflavone, paclitaxel and camptothecin in human breast cancer cells.
OBJECTIVE
Aminoflavone is a unique DNA damaging agent currently undergoing phase I evaluation in a prodrug form (AFP464). In anticipation of combination regimens, interactions between aminoflavone and several anticancer drugs were investigated in MCF-7 breast cancer cells to determine whether synergistic cancer cell killing effects were observed.


METHODS
Colony formation assays were performed to assess the effect of combining aminoflavone with a variety of anticancer drugs. Changes in initial uptake, retention or efflux of aminoflavone and the second agent were compared to the behavior of drugs alone. Key features required for aminoflavone activity in cell culture models were also explored, focusing on the obligatory induction of CYP1A1/1A2 and binding of reactive aminoflavone metabolites to tumor cell total macromolecules and DNA.


RESULTS
Aminoflavone was synergistic when co-incubated with paclitaxel, camptothecin or SN38. Uptake of neither aminoflavone nor any of the other three compounds was altered in combination incubations. Paclitaxel did not inhibit DNA binding of aminoflavone metabolites, while camptothecin did. Aminoflavone-induced CYP1A1 induction was observed in the presence of camptothecin or paclitaxel.


CONCLUSIONS
Aminoflavone is a promising therapeutic agent for breast cancer due to its unique mechanism of action compared to commonly used drugs. Combined treatments utilizing aminoflavone in conjunction with paclitaxel or camptothecin may provide an even greater cytotoxic effect than achieved with aminoflavone alone.
Reinicke
Kathryn E
KE
Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
Kuffel
Mary J
MJ
Goetz
Matthew P
MP
Ames
Matthew M
MM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay / Q000379:methods; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000187:drug effects*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D017239:Paclitaxel / Q000008:administration & dosage
D005419:Flavonoids; C413760:aminoflavone; D000077146:Irinotecan; D004247:DNA; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D017239:Paclitaxel; D002166:Camptothecin