We and others have shown that the copper transporters ATP7A and ATP7B play a role in cellular resistance to cisdiaminedichloroplatinum (II) (CDDP). In this study, we found that ATP7A transfection of Chinese hamster ovary cells (CHO-K1) and fibroblasts isolated from Menkes disease patients enhanced resistance not only to CDDP but also to various anticancer drugs, such as vincristine, paclitaxel, 7-ethyl-

Anthocyanidins, which are polyphenols that are believed to be effective for preventing cancer, are composed of a basic structure of the plant pigment anthocyanin. In this study, we investigated the biological activity of anthocyanidins, including delphinidin, against HeLa cells. The cytotoxicity observed in the anthocyanidins-treated cells was well correlated with the inhibitory effects of anthocyanidins on c-Jun-dependent transcriptional activity. Remarkably, anthocyanidin induced autophagosome formation but lacked the ability to induce apoptosis. Notably, delphinidin enhanced autolysosome formation as well as autophagosome formation. Delphinidin treatment resulted in the accumulation of the lipidated form of Map1lc3b protein in an Atg5-dependent manner in mouse embryonic fibroblasts. Finally, we revealed that the cytotoxicity induced by delphinidin was more severe in Atg5-deficient mouse embryonic fibroblasts than in wild-type cells. Taken together, these results indicate that the cytotoxicity induced by delphinidin was accompanied by autophagy and delphinidin-induced autophagy exerted a cell protective role.

Supplementary Figure 1A from Copper-Transporting P-Type ATPase, ATP7A, Confers Multidrug Resistance and Its Expression Is Related to Resistance to SN-38 in Clinical Colon Cancer

<div>Abstract<p>We and others have shown that the copper transporters ATP7A and ATP7B play a role in cellular resistance to <i>cis</i>-diaminedichloroplatinum (II) (CDDP). In this study, we found that <i>ATP7A</i> transfection of Chinese hamster ovary cells (CHO-K1) and fibroblasts isolated from Menkes disease patients enhanced resistance not only to CDDP but also to various anticancer drugs, such as vincristine, paclitaxel, 7-ethyl-10-hydroxy-camptothecin (SN-38), etoposide, doxorubicin, mitoxantron, and 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11). ATP7A preferentially localized doxorubicin fluorescence to the Golgi apparatus in contrast to the more intense nuclear staining of doxorubicin in the parental cells. Brefeldin A partially and monensin completely altered the distribution of doxorubicin to the nuclei in the ATP7A-expressing cells. ATP7A expression also enhanced the efflux rates of doxorubicin and SN-38 from cells and increased the uptake of SN-38 in membrane vesicles. These findings strongly suggested that ATP7A confers multidrug resistance to the cells by compartmentalizing drugs in the Golgi apparatus and by enhancing efflux of these drugs, and the <i>trans</i>-Golgi network has an important role of ATP7A-related drug resistance. ATP7A was expressed in 8 of 34 (23.5%) clinical colon cancer specimens but not in the adjacent normal epithelium. Using the histoculture drug response assay that is useful for the prediction of drug sensitivity of clinical cancers, ATP7A-expressing colon cancer cells were significantly more resistant to SN-38 than ATP7A-negative cells. Thus, ATP7A confers resistance to various anticancer agents on cancer cells and might be a good index of drug resistance in clinical colon cancers. [Cancer Res 2007;67(10):4860–7]</p></div>

Supplementary Table 1 from Copper-Transporting P-Type ATPase, ATP7A, Confers Multidrug Resistance and Its Expression Is Related to Resistance to SN-38 in Clinical Colon Cancer