HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells
BRCA1 is a protein that plays a critical role in several cellular processes, including DNA damage response and repair, homologous recombination, regulation of the cell cycle, and programmed cell death known as apoptosis. Ovarian cancers with mutations in the BRCA1 gene are often diagnosed at a later stage. However, these cancers tend to show a better initial response to chemotherapy regimens that include platinum-based drugs when compared to ovarian cancers without BRCA1 mutations. Despite this initial sensitivity, most patients with BRCA1-mutated ovarian cancer will experience a recurrence of the disease and eventually succumb to it.
Current preclinical research is exploring the potential of natural compounds and their synthetic analogs as targeted therapies for ovarian cancer. The primary objective of this study was to determine if HO-3867, a novel analog of curcumin that inhibits the STAT3 signaling pathway, could have a therapeutic effect on ovarian cancer cells harboring BRCA1 mutations. Our novel compound, HO-3867, as well as a commercially available STAT3 inhibitor called STATTIC, significantly inhibited the growth of BRCA1-mutated ovarian cancer cells in laboratory experiments.
This inhibition was observed to be dependent on both the concentration of the inhibitor used and the duration of treatment. BRCA1-mutated ovarian cancer cells that were treated with HO-3867 showed a significant increase in apoptosis, as indicated by elevated levels of cleaved caspase-3, caspase-7, and PARP, which are proteins involved in the apoptotic process. Treatment with HO-3867 induced a greater production of reactive oxygen species in BRCA1-mutated cancer cells compared to cancer cells with normal BRCA1 function. However, benign ovarian surface epithelial cells did not show an increase in reactive oxygen species when treated with HO-3867.
We also found that BRCA1-mutated cancer cells had higher levels of a specific activated form of the STAT3 protein, known as Tyrosine-phosphorylated STAT3 (pTyr705), compared to other STAT proteins. Furthermore, treating these cells with HO-3867 resulted in a decrease in the expression of pTyr705 and its downstream target proteins, including cyclin D1, Bcl-2, and survivin, which are involved in cell cycle progression and the inhibition of apoptosis. Additionally, when the STAT3 gene was artificially overexpressed in these cancer cells, it provided them with resistance to the apoptosis-inducing effects of HO-3867.
Taken together, our results suggest that HO-3867, a potent inhibitor of the STAT3 signaling pathway, may have potential as a biologically targeted therapeutic agent for cancers with BRCA1 mutations, either as an addition to standard cytotoxic chemotherapy or as a standalone treatment.