Synergetic cytotoxic activity toward breast cancer cells enhanced by the combination of Antp-TPR hybrid peptide targeting Hsp90 and Hsp70-targeted peptide.

Abstract

BACKGROUND:

Heat shock protein (Hsp) 90 and Hsp70 are indispensable for cell survival under conditions of stress. They bind to client proteins to assist in protein stabilization, translocation of polypeptides across the cell membrane, and recovery of proteins from aggregates in the cell. Therefore, these proteins have recently emerged as important targets in the treatment of cancer. We previously reported that the newly designed Antp-TPR hybrid peptide targeting Hsp90 induced cytotoxic activity to cancer cells both in vitro and in vivo.

METHODS:

To further improve the cytotoxic activity of Antp-TPR toward cancer cells, we investigated the effect of a Hsp70-targeted peptide, which was made cell-permeable by adding the polyarginine with a linker sequence, on the cytotoxic activity of Antp-TPR in breast cancer cell lines.

RESULTS:

It was revealed that Antp-TPR in the presence of a Hsp70-targeted peptide induced effective cytotoxic activity toward breast cancer cells through the descrease of Hsp90 client proteins such as p53, Akt, and cRaf. Moreover, the combined treatment with these peptides did not induce the up-regulation of Hsp70 protein, as determined by western blotting, a promoter assay using a luminometer, and single-cell level imaging with the LV200 system, although a small-molecule inhibitor of Hsp90, 17-allylamino-demethoxygeldanamycin (17-AAG), did induce the up-regulation of this protein. We also found that treatment with Antp-TPR, Hsp70-targeted peptide, or a combination of the two did not induce an increase in the glutathione concentrations in the cancer cells.

CONCLUSION:

These findings suggest that targeting both Hsp90 and Hsp70 with Antp-TPR and Hsp70-targeted peptide is an attractive approach for selective cancer cell killing that might provide potent and selective therapeutic options for the treatment of cancer.

• Authors: Tomohisa Horibe, Aya Torisawa, Masayuki Kohno, Koji Kawakami
• Journal: BMC cancer (BMC Cancer) Vol. 14 Pg. 615 (Aug 26 2014) ISSN: 1471-2407 [Electronic] England
• PMID: 25159299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antennapedia Homeodomain Protein
• Antineoplastic Agents
• Benzoquinones
• HSP70 Heat-Shock Proteins
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Nuclear Pore Complex Proteins
• Peptides
• tanespimycin

Topics

• Antennapedia Homeodomain Protein (chemistry)
• Antineoplastic Agents (pharmacology)
• Benzoquinones (pharmacology)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HSP70 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Lactams, Macrocyclic (pharmacology)
• Molecular Targeted Therapy
• Nuclear Pore Complex Proteins (chemistry)
• Peptides (chemical synthesis, pharmacology)
• Signal Transduction (drug effects)