Abstract:
:Standard chemotherapeutic protocols, based on maximum tolerated doses, do not prevent nor overcome chemoresistance caused by the efflux transporter P-glycoprotein (Pgp). We compared the effects of two consecutive low doses versus a single high dose of doxorubicin in drug-sensitive Pgp-negative and drug-resistant Pgp-positive human and murine cancer cells. Two consecutive low doses were significantly more cytotoxic in vitro and in vivo against drug-resistant tumors, while a single high dose failed to do so. The greater efficacy of two consecutive low doses of doxorubicin could be linked to increased levels of intracellular reactive oxygen species. These levels were produced by high electron flux from complex I to complex III of the mitochondrial respiratory chain, unrelated to the synthesis of ATP. This process induced mitochondrial oxidative damage, loss of mitochondrial potential and activation of the cytochrome c/caspase 9/caspase 3 pro-apoptotic axis in drug-resistant cells. Our work shows that the "apparent" ineffectiveness of doxorubicin against drug-resistant tumors overexpressing Pgp can be overcome by changing the timing of its administration and its doses.
journal_name
Cancer Lettjournal_title
Cancer lettersauthors
Riganti C,Gazzano E,Gulino GR,Volante M,Ghigo D,Kopecka Jdoi
10.1016/j.canlet.2015.02.008subject
Has Abstractpub_date
2015-05-01 00:00:00pages
219-26issue
2eissn
0304-3835issn
1872-7980pii
S0304-3835(15)00099-3journal_volume
360pub_type
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