A Correlation between Cytotoxicity and Reductase-Mediated Metabolism in Cell Lines Treated with Doxorubicin and Daunorubicin

Abstract

The role of metabolism in daunorubicin (DAUN)-and doxorubicin (DOX)-associated toxicity in cancer patients is dependent on whether the parent drugs or major metabolites, doxorubicinol (DOXol) and daunorubicinol (DAUNol), are the more toxic species. Therefore, we examined whether an association exists between cytotoxicity and the metabolism of these drugs in cell lines from nine different tissues. Cytotoxicity studies using MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide] cell viability assays revealed that four cell lines [HepG2 (liver), HCT-15 (colon), NCI-H460 (lung), and A-498 (kidney)] were more tolerant to DAUN and DOX than the five remaining cell lines [H9c2 (heart), PC-3 (prostate), OVCAR-4 (ovary), PANC-1 (pancreas), and MCF-7 (breast)], based on significantly higher LC 50 values at incubation times of 6, 24, and 48 hours. Each cell line was also assessed for its efficiency at metabolizing DAUN and DOX. The four drug-tolerant cell lines converted DAUN/DOX to DAUNol/DOXol more rapidly than the five drug-sensitive cell lines. We also determined whether exposure to DAUN or DOX induced an increase in metabolic activity among any of these nine different cell types. All nine cell types showed a significant increase in their ability to metabolize DAUN or DOX in response to pre-exposure to the drug. Western blot analyses demonstrated that the increased metabolic activity toward DAUN and DOX correlated with a greater abundance of eight aldo-keto and two carbonyl reductases following exposure to either drug. Overall, our findings indicate an inverse relationship between cytotoxicity and DAUN or DOX metabolism in these nine cell lines.

Curcumin is a tight-binding inhibitor of the most efficient human daunorubicin reductase – Carbonyl reductase 1

“…Interestingly, a study of Bains et al provides evidence that eight aldo-keto reductase and two carbonyl reductase isoforms are upregulated after pre-exposure to DAUN or DOX [20]. Thus, elevated enzymatic reduction of DAUN or DOX may also be part of the mechanisms that cause pharmacokinetic anthracycline resistance in tumors.…”

“…Convincing evidence supports the idea that the C-13 hydroxy metabolites of DAUN and DOX, daunorubicinol (DAUNOL) and doxorubicinol (DOXOL), respectively, are the main trigger for chronic cardiotoxicity [16][17][18][19][20][21]. Thus, inhibition of CBR1 may increase the efficacy and decrease cardiotoxicity of anthracyclines [7,22,23].…”

Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents

“…Among these, there are ACEi, ARBs, renin and β1 antagonist, NO donor drugs, PKCε agonist and ALDH2 activators. (VEGF: vascular endothelial growth factor; BK: bradykinin; SP: substance P; NO: nitric oxide; ET: endothelin; PGI2: prostacyclin; AngII: angiotensin II; MAPK: Mitogen activated proteine kinase; cGMP: cyclic guanosine monophosphate; FGF2: fibroblast growth factor; VSMCs: vascular smooth muscle cells) Anthracycline-induced endothelial toxicity seems to be a complex response, influenced by various mechanisms, including drug-accumulation in nuclei [14] and mitochondria [15], and DNA repair [16], stress-induced signaling mechanisms [17], sarcoplasmic reticulum stress [18], nitrosative stress [19], the activity on drug transporters (including MDR1 and MRP1) [20], drug metabolism [21], and TopI and II inhibition [15,22].…”

Single nucleotide polymorphisms in ABCB1 and CBR1 can predict toxicity to R-CHOP type regimens in patients with diffuse non-Hodgkin lymphoma

“…Lars P. Jordheim, 1,2,3 Vincent Ribrag, 4 Hervé Ghesquieres, 5 Sophie Pallardy, 6 Richard Delarue, 7 Hervé Tilly,8 Corinne Haioun, 9 Fabrice Jardin, 10 Delphine Demangel, 2,3 Gilles A. Salles 11 …”

“…7 CBR1 has also been suspected to be involved in the occurrence of anthracycline-related toxicities as non-synonymous SNP were associated with reduced metabolism of doxorubicin and daunorubicin, and as these metabolisms were correlated to the expression of carbonyl reductases. 8,9 In addition, polymorphisms in CBR1 were correlated with altered pharmacokinetics with increased exposure to doxorubicin. 10 Finally, the cardioprotectant flavonoid 7-monohydroxyethyl rutoside was shown to behave as a CBR1 inhibitor.…”