Abstract
BOLD-100, a ruthenium-based complex, sodium trans-[tetrachloridobis (1H-indazole) ruthenate (III)] (also known as IT-139, NKP1339 or KP1339), is a novel small molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity in a phase I clinical trial. BOLD-100 has been reported to inhibit the upregulation of the endoplasmic reticulum stress sensing protein GRP78. However, response to BOLD-100 varies in different cancer models and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that BOLD-100 induces cytostatic rather than cytotoxic effects as a monotherapy. To understand BOLD-100-mediated signaling mechanism in breast cancer cells, we used estrogen receptor positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models. At 100 µM, BOLD-100 significantly reduced cell proliferation and expression of genes involved in the DNA repair pathway. BOLD-100 also induced reactive oxygen species (ROS) and phosphorylation of histone H2AX, gamma-H2AX (Ser139), suggesting disruption of proper DNA surveillance. In estrogen receptor negative (ER−) breast cancer cells, combination of BOLD-100 with a PARP inhibitor, olaparib, induced significant inhibition of cell growth and xenografts and increased gamma-H2AX. Thus, BOLD-100 is a novel DNA repair pathway targeting agent and can be used with other chemotherapies in ER− breast cancer.
| Original language | English (US) |
|---|---|
| Article number | 2647 |
| Pages (from-to) | 1-19 |
| Number of pages | 19 |
| Journal | Cancers |
| Volume | 12 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2020 |
| Externally published | Yes |
Bibliographical note
Funding Information:Conflicts of Interest: S.B. was formerly employed by Intezyne Technologies, Inc., and is currently a Consultant for Bold Therapeutics, Inc. S.B. contributed to concept design, revision and final approval of present article. A.S.-H. has received a research grant from Intezyne Technologies, Inc. to partly support this project. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding Information:
Funding: This work was partly supported by Public Health Service NIH grant R01CA201092 to ANS-H. Technical services were provided by the following shared resources at Georgetown University Medical Center: Genomics and Epigenomics, Flow Cytometry and Tissue Culture Core Shared Resources that were funded through NIH grant 1P30-CA-51008 (Lombardi Comprehensive Cancer Center Support Grant). RPPA data was generated with support from NIH grant CA16672 (MD Anderson Cancer Center).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
- BOLD-100
- Breast cancer
- Olaparib
- Triple negative breast cancer
