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causing the increased leakage of electrons generated by the oxidative phosphorilation
process. These electrons will rapidly react with molecular oxygen producing reactive
oxygen species (ROS) (Gille and Nohl 1997). Another pathway of adriamycin-induced
apoptosis was described in isolated adult cardiac myocytes (Andrieu-Abadie et al.1999;
Henaff et al. 2002). Adriamycin has a potential tp activate acidic sphlingomyelinase
which will result in the increased production of ceramide (Andrieu-Abadie et al. 1999).
The increase in the intracellular levels of ceramide will lead to the activation of
mitochondrial membrane voltage-independent B type calcium charmels which will result
in the opening of mitochondrial transition pores and release of cytochrome C (Andrieu-
Abadie et al. 1999). This hypothesis is confirmed by the reports that carnitine, an
inhibitor of acid sphl'ngomyelinase, has a potential to inhibit adriamycin-induced
apoptosis.
Adriamycin administration was also found to cause the activation of proapoptotic
factor-p38 mitogen activated protein kinases (MAPK), while the inhibitors of p38 MAPK
were found to prevent the occurrence of adriamycin-induced apoptosis in cardiac
myocytes (Kang et al. 2000b). Adriamycin-induced activation of p38 was prevented by a
cardiac-specific overexpression of antioxidant compounds metatallothioenins thus linking
the adriamycin-induced oxidative stress with p38 initiated apoptosis in cardiac myocytes
(Kang et al. 2000b).
The involvement of oxidative stress in the pathogenesis of adriamycin-induced
apoptosis in isolated cardiac myocytes was also confirmed in a study where treatments
with antioxidant trolox prevented the development of adriamycin-induced apoptosis
(Kumar et al. 1999). It is interesting to mention that the exposure of isolated cardiac
t5