Melding epigenetic inhibitors with the calpain inhibitor calpeptin may be a promising combination therapy approach to treat ovarian cancer patients, including those who are resistant to platinum-based chemotherapy, a new AntiCancer Research study suggests.
The study, “The Effects of Histone Deacetylase Inhibitor and Calpain Inhibitor Combination Therapies on Ovarian Cancer Cells,” revealed that treating ovarian cancer cells with suboptimal doses of sodium butyrate, SAHA, and calpeptin, has a synergistic effect in tumor cell growth inhibition and tumor cell death.
Ovarian cancer is the most deadly cancer of the reproductive system, in part because it is often detected in an advanced state, where the cancer cells have already spread whithin the pelvis and abdomen.
Platinum-based chemotherapy has been the mainstay for the past four decades in the treatment of ovarian cancer, regardless of the cancer subtype, mutational status, or biomarkers, but patients often develop resistance to such drugs, revealing the need for novel treatment approaches.
In recent years, epigenetics has been proposed as a new target to overcome drug resistance. Epigenetics are modifications in the DNA that do not change its sequence, but that determine which genes will be expressed by which cells at any given time. Since all cells in an organism share the same DNA sequence, epigenetics is what determines that a liver cell is a liver cell, and not a lung cell, for example.
The authors of this study had previously shown that epigenetics play a major role in the formation of cancer progenitor cells, cancer progression, metastasis and cancer drug resistance. Consistently, epigenetic drugs were found to sensitize platinum-resistance ovarian cancer cells and promote the death of breast cancer.
However, when the researchers combined calpeptin with histone deacetylase inhibitors (epigenetic drugs) in breast cancer cells, they saw a stronger anti-tumor effect than when epigenetic drugs were used alone.
Based on results suggesting that breast and ovarian cancer have a common epigenetic origin, sharing many genetic and epigenetic events, the researchers sought to examine whether this combination also was effective in ovarian cancer cells.
They found that suboptimal doses of the epigenetic drugs sodium butyrate and SAHA combined with the calpain inhibitor calpeptin enahnced the cell growth inhibition and promoted tumor cell death.
Calpain is an enzyme that regulates many signaling proteins and pathways and that have been implicated in cancer progression. But when the researchers looked at how calpeptin was working in tumor cells, they found this inhibitor also could function as an epigenetic drug.
“Calpeptin possibly has a dual role. It can kill cancer cells and in addition it may act as an epigenetic drug as well,” Sibaji Sarkar, PhD, instructor of medicine, Boston University School of Medicine, said in a press release. “We believe that epigenetic drugs alone are not the best choice for cancer therapy. We need other target-specific and other types of inhibitors but the addition of epigenetic drugs can increase the efficacy of the therapy, inhibiting formation of new cancer progenitor/stem cells by re-expressing tumor suppressor genes and blocking the expression of growth promoting genes even after remission after standard therapy,” said Sarkar.
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