Breast cancer is the most common cancer in women. Most breast tumors are ER(+)/hormone-dependent, this makes it possible to treat them with tamoxifen and other SERM/SERD drugs. Combination treatment of tamoxifen with novel drugs provides an efficient way for reduction of the drug concentration. The aim of the work was to obtain novel less toxic oligomycin derivatives for combinatorial treatment with tamoxifen.
Oligomycin A was produced at BIOAN (Moscow, Russia) using Streptomyces avermitilis NIC B62. The oligomycin derivatives were synthesized from oligomycin A. MCF-7 breast cancer cell line and MCF-10A human mammary epithelial cell line were obtained from the ATCC collection. Hormone-resistant subline was developed by long-term treatment of MCF-7 line with tamoxifen. Antiproliferative activity was measured by MTT.
A series of less toxic oligomycin A derivatives, selectively modified at the C-33 position of the side chain, was synthesized, and their activity against hormone-dependent breast cancer cells was tested. Lead compound, a (33S)-diastereomer of oligomycin A (epi-oligomycin A), was chosen, which showed high activity towards MCF-7 breast cancer cells and MCF-7/TR hormone-resistant cells. Low doses of tamoxifen and epi-oligomycin A, which had no significant effects on the growth of MCF-7 cells, were evaluated. In combination, low doses of tamoxifen and epi-oligomycin A caused a significant antiproliferative effects on MCF-7 cells. Moreover, it was possible to return the sensitivity of hormone-resistant subline to tamoxifen by epi-oligomycin A treatment. Non-malignant epithelial cells, MCF-10A, were less sensitive to epi-oligomycin A.
Novel epi-oligomycin A enhances response to tamoxifen, which allows for reduction of the effective drug concentration. Combinatorial strategy with epi-oligomycin A may hold promise in development of therapies against breast tumours, including those with acquired resistance to the hormonal treatment. The research is supported by Russian Science Foundation (chemistry, agreement 15-15-00141) and the Russian Foundation for Basic Research (biology, 18-015-00422).
The authors.
Russian Science Foundation (chemistry, agreement 15-15-00141) and the Russian Foundation for Basic Research (biology, 18-015-00422).
All authors have declared no conflicts of interest.