Abstract
Doxorubicin is a frequently used anticancer drug to treat many types of tumors, such as breast cancer or bronchial carcinoma. The clinical use of doxorubicin is limited by its poorly predictable cardiotoxicity, the reasons of which are so far not fully understood. The drug is a substrate of several efflux transporters such as P-gp or BCRP and was recently reported to be a substrate of cation uptake transporters. To evaluate the potential role of transporter proteins in the accumulation of doxorubicin at its site of action (e.g., mammary carcinoma cells) or adverse effects (e.g., heart muscle cells), we studied the expression of important uptake and efflux transporters in human breast cancer and cardiac tissue, and investigated the affinity of doxorubicin to the identified transporters. The cellular uptake studies on doxorubicin were performed with OATP1A2*1, OATP1A2*2, and OATP1A2*3-overexpressing HEK293 cells, as well as OCT1-, OCT2-, and OCT3- overexpressing MDCKII cells. To assess the contribution of transporters to the cytotoxic effect of doxorubicin, we determined the cell viability in the presence and absence of transporter inhibitors in different cell lines. Several transporters, including P-gp, BCRP, OCT1, OCT3, and OATP1A2 were expressed in human heart and/or breast cancer tissue. Doxorubicin could be identified as a substrate of OCT1, OCT2, OCT3, and OATP1A2. The cellular uptake into cells expressing genetic OATP1A2 variants was markedly reduced and correlated well with the increased cellular viability. Inhibition of OATP1A2 (naringin) and OCT transporters (1-methyl-4-phenylpyridinium) resulted in a significant decrease of doxorubicin-mediated cytotoxicity in cell lines expressing the respective transporters. Similarly, the excipient Cremophor EL significantly inhibited the OCT1-3- and OATP1A2-mediated cellular uptake and attenuated the cytotoxicity of doxorubicin. In conclusion, genetic and environmental-related variability in the expression and function of these transporters may contribute to the substantial variability seen in terms of doxorubicin efficacy and toxicity.
Highlights
The anthracycline antibiotic doxorubicin is an antineoplastic drug frequently used for the effective treatment of many solid tumors, including lung, ovarian, gastric, and breast cancer, as well as hematological malignancies such as lymphoma, acute leukemia, and multiple myeloma
On the mRNA level, the efflux transporters ABCB1, ABCC1, and ABCG2 were found expressed in human heart, in normal and tumorous breast tissue, and in human breast expressed in human heart, in normal and tumorous breast tissue, and in human breast cancer cell lines MCF-7, MDA-MB-231, and ZR-75-1 (Figure 1)
In breast cancer cell lines, SLC22A1 was only expressed in MCF-7 and ZR-75-1 cells, while SLC22A3 was exclusively expressed in MDA-MB-231 cells
Summary
The anthracycline antibiotic doxorubicin is an antineoplastic drug frequently used for the effective treatment of many solid tumors, including lung, ovarian, gastric, and breast cancer, as well as hematological malignancies such as lymphoma, acute leukemia, and multiple myeloma. The cytotoxic mode of action of doxorubicin is complex, and includes its intercalation into the DNA, leading to DNA strand breakage, inhibition of DNA- and RNApolymerases, inhibition of DNA-topoisomerase II, and formation of free radicals. One of the most serious and dose-limiting side effects of doxorubicin is irreversible cardiotoxicity leading to dilated cardiomyopathy and congestive heart failure, the reasons of which are still not fully understood [3,5,6,7]. Doxorubicin is assumed to cause cardiomyopathy by inducing oxidative stress (via the formation of free radicals) and p53-mediated apoptosis. To avoid doxorubicin-related cardiotoxicity, the cumulative dose may not exceed
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