Vincristine attenuates doxorubicin cardiotoxicity.
Our aim was to test the hypothesis that the vinca alkaloid vincristine could prevent doxorubicin-induced cardiomyocyte death and to identify the mechanisms involved. Adult mouse cardiac myocytes were incubated for 24 h with doxorubicin, with and without concurrent vincristine. Trypan blue exclusion showed that 50-60% of myocytes treated with doxorubicin alone survived. Concurrent vincristine treatment increased survival to 85%. Treatment with doxorubicin+vincristine activated the prosurvival signal Akt and diminished cytochrome C release. The PI3K/Akt inhibitor LY294002 and the MEK/ERK inhibitor PD98059 augmented doxorubicin cardiotoxicity and attenuated salvage during concurrent vincristine treatment, indicating that the mechanism of vincristine cardioprotection involves activation of specific survival signals. Vincristine retarded the onset of apoptosis in association with a delay in poly(ADP) ribose polymerase activation. Vincristine also exhibited greater protection than the antioxidant MPG. These novel findings may have clinical implications for the prevention of doxorubicin cardiomyopathy.
Chatterjee
Kanu
K
Cardiology Division, University of California, 505 Parnassus Avenue, San Francisco, California 94122, USA.
Zhang
Jianqing
J
Tao
Rong
R
Honbo
Norman
N
Karliner
Joel S
JS
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D004317:Doxorubicin / Q000633:toxicity*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D002867:Chromones; D045304:Cytochromes c; D004317:Doxorubicin; D005419:Flavonoids; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D014750:Vincristine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one