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PA-MSHA inhibits the growth of doxorubicin-resistant MCF-7/ADR human breast cancer cells by downregulating Nrf2/p62.

ABSTRACT: Acquired resistance to doxorubicin in breast cancer is a serious therapeutic problem. In this study, we investigated whether Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) could inhibit the growth of doxorubicin-resistant breast cancer cells. We found that the expressions of Nrf2 and p62 in breast cancer were higher than that in the corresponding adjacent normal tissues and benign breast epithelial cell. The expressions of Nrf2 and p62 in breast cancer doxorubicin-resistant cells MCF-7/ADR were higher than that in doxorubicin-sensitive cells MCF-7. Silencing of Nrf2 or p62 rendered breast cancer cells more susceptible to doxorubicin. We further demonstrated that PA-MSHA inhibited growth and induced apoptosis of MCF-7/ADR cells but not MCF-7 cells. Subcutaneous administration of PA-MSHA greatly inhibited the growth of xenograft tumors from MCF-7/ADR cells in nude mice. In addition, PA-MSHA could downregulate Nrf2 and p62 in vitro and in vivo. These results suggested that activation of Nrf2 and p62 was associated with doxorubicin resistance in breast cancer. PA-MSHA could inhibit the growth of doxorubicin-resistant MCF-7/ADR cells and its potential mechanism might be due to the suppression of Nrf2/p62. It indicated the possibility of using PA-MSHA in doxorubicin-resistant breast cancer.

SUBMITTER: Wei Y

PROVIDER: S-EPMC5224842 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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PA-MSHA inhibits the growth of doxorubicin-resistant MCF-7/ADR human breast cancer cells by downregulating Nrf2/p62.

Wei Yingze Y Liu Danyang D Jin Xiaoxia X Gao Pan P Wang Qingying Q Zhang Jiawen J Zhang Nong N

Cancer medicine 20161018 12

Acquired resistance to doxorubicin in breast cancer is a serious therapeutic problem. In this study, we investigated whether Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) could inhibit the growth of doxorubicin-resistant breast cancer cells. We found that the expressions of Nrf2 and p62 in breast cancer were higher than that in the corresponding adjacent normal tissues and benign breast epithelial cell. The expressions of Nrf2 and p62 in breast cancer doxorubicin-resistant cel ...[more]

PMID: 27758045

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Project description:Clotted plasma proteins are present on the walls of tumor vessels and in tumor stroma. Tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA) could recognize the clotted plasma proteins in tumor vessels. Thermosensitive liposomes could immediately release the encapsulated drug in the vasculature of the heated tumor. In this study, we designed a novel form of targeted thermosensitive liposomes, CREKA-modified lysolipid-containing thermosensitive liposomes (LTSLs), containing doxorubicin (DOX) (DOX-LTSL-CREKA), to investigate the hypothesis that DOX-LTSL-CREKA might target the clotted plasma proteins in tumor vessels as well as tumor stroma and then exhibit burst release of the encapsulated DOX at the heated tumor site. We also hypothesized that the high local drug concentration produced by these thermosensitive liposomes after local hyperthermia treatment will be useful for treatment of multidrug resistance. The multidrug-resistant human breast adenocarcinoma (MCF-7/ADR) cell line was chosen as a tumor cell model, and the targeting and immediate release characteristics of DOX-LTSL-CREKA were investigated in vitro and in vivo. Furthermore, the antitumor activity of DOX-LTSL-CREKA was evaluated in MCF-7/ADR tumor-bearing nude mice in vivo. The targeting effect of the CREKA-modified thermosensitive liposomes on the clotted plasma proteins was confirmed in our in vivo imaging and immunohistochemistry experiments. The burst release of this delivery system was observed in our in vitro temperature-triggered DOX release and flow cytometry analysis and also by confocal microscopy experiments. The antitumor activity of the DOX-LTSL-CREKA was confirmed in tumor-bearing nude mice in vivo. Our findings suggest that the combination of targeting the clotted plasma proteins in the tumor vessel wall as well as tumor stroma by using CREKA peptide and temperature-triggered drug release from liposomes by using thermosensitive liposomes offers an attractive strategy for chemotherapeutic drug delivery to tumors.

Dataset Information

PA-MSHA inhibits the growth of doxorubicin-resistant MCF-7/ADR human breast cancer cells by downregulating Nrf2/p62.

Publications

PA-MSHA inhibits the growth of doxorubicin-resistant MCF-7/ADR human breast cancer cells by downregulating Nrf2/p62.

Similar Datasets

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