posted on 2021-06-07, 23:43authored byBrian Kawahara, Kym F. Faull, Carla Janzen, Pradip K. Mascharak
Paclitaxel (PTX) is a first-line
treatment in breast cancer, though
resistance develops quickly and frequently. Cytochrome P450 enzymes
CYP3A4 and CYP2C8, which metabolically inactivate PTX in hepatic tissue,
are overexpressed in malignant breast tissues. CYP3A4 expression correlates
with PTX therapy failure and poor outcomes, though no direct evidence
of CYP3A4 contributing to PTX sensitivity exists. Because CYP3A4/2C8
is susceptible to carbon monoxide (CO)-mediated inhibition and CO
(a gaseous signaling molecule) has previously exhibited drug-sensitizing
effects in cancer cells, we hypothesized that CO-mediated inhibition
of CYP3A4/2C8 could lead to enhanced drug sensitivity. Using a photo-activated
CO-releasing molecule, we have assessed the ability of CO to alter
the pharmacokinetics of PTX in breast cancer cells via inhibition
of CYP3A4/2C8 and determined that CO does enhance sensitivity of breast
cancer cells to PTX. Inhibition of CYP3A4/2C8 by CO could therefore
be a promising therapeutic strategy to enhance PTX response in breast
cancer.