Enhancing BH3 Mimetic Therapy for Melanoma
Posted: Wednesday, December 5, 2018
Inhibition of major antiapoptotic proteins may be sufficient to kill both melanoma-initiating cells and the bulk of melanoma cells. In a new study published in Cell Death and Disease, Nabanita Mukherjee, PhD, of the University of Colorado School of Medicine, and her colleagues found that the combination of BH3 mimetics with A-1210577 (MCL-1 inhibitor) and ABT-263 (BCL2/BCL-XL/BCL-W inhibitor) kill melanoma cell lines regardless of mutation status or relapsed state.
“In cancer cells, there is a mix of pro-death and anti-death proteins. Depending on the balance, these cells live or die,” said Dr. Mukherjee in an interview with the University of Colorado’s Garth Sundem. “By using navitoclax [BH3 mimetic] and A-1210477 to mute BCL-2 and MCL-1, we remove anti-death proteins and, on balance, cancer cells die.”
Several different patient samples of melanoma with diverse genetic backgrounds were utilized in the study for clinical significance. Researchers employed cell viability, apoptosis, bright field, immunoblot, and sphere formation assays in addition to clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome-editing to determine the apoptotic effects of the combination therapy.
The mixture of these three drugs used was found to hinder the activation of DRP-1, helping to enhance apoptosis in a mechanism not seen in other types of cancer cells. The team concluded that DRP-1 inhibition may therefore be a target for BH3 mimetics in melanoma.