Bovine serum amine oxidase and spm potentiate docetaxel and interferon-alpha effects in inducing apoptosis on human cancer cells through the generation of oxidative stress.
It was previously demonstrated that bovine serum amine-oxidase (BSAO) and SPM (SPM) addition to cancer cells induces cell growth inhibition and over-run the multi-drug resistance (MDR) phenotype through the oxidative stress caused by polyamine metabolites. In this study, it is reported that BSAO/SPM enzymatic system antagonizes the survival pathway induced by either docetaxel (DTX) or interferon alpha (IFNalpha) in human epidermoid cancer KB cells. The combination of BSAO/SPM with either DTX or IFNalpha had a synergistic effect on cell growth inhibition through apoptosis in both human epidermoid KB and breast cancer MCF-7 cell lines. The effects of the BSAO/SPM-DTX combination on apoptosis were caspase 3 and 9-dependent and were paralleled by the enhancement of intracellular O(2-), nitric oxide levels and of lipo-oxidation. The scavenger moiety N-acetyl-cysteine antagonized the effects on apoptosis and cell growth inhibition induced by the combination suggesting a role of the oxidative products of SPM. These effects occurred together with a decrease of the physiological scavenger MnSOD and an increase of both p38 kinase activity and DNA damage. The results suggest that DTX and IFNalpha could sensitize tumour cells to the oxidative stress and apoptosis induced by BSAO/SPM through the induction of a survival ras-dependent pathway and the consequent elevation of the intracellular polyamine pool. These data allow the design of new therapeutic strategy based on the use of this combination in human neoplasms.
Marra
M
M
Department of Biochemistry and Biophysics, School of Medicine, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
Lombardi
A
A
Agostinelli
E
E
Giuberti
G
G
Zappavigna
S
S
Tempera
G
G
Vitale
G
G
Bifulco
M
M
Abbruzzese
A
A
Caraglia
M
M
D006631:Amine Oxidase (Copper-Containing) / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D015227:Lipid Peroxidation; D009569:Nitric Oxide / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D013096:Spermine / Q000494:pharmacology*; D013482:Superoxide Dismutase; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000473:pathology; D018631:ras Proteins
D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D043823:Taxoids; D000077143:Docetaxel; D013096:Spermine; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D006631:Amine Oxidase (Copper-Containing); D051058:Oncogene Protein v-akt; D053148:Caspase 3; D018631:ras Proteins