The novel cardio‐oncology drug, NP‐6A4, regulates the growth of multiple breast cancer cell lines through distinct cell‐specific mechanisms

Abstract

While chemotherapeutic agents (anthracyclins, kinase‐inhibitors) have improved 5‐year breast cancer survival, their cardiovascular toxicity cause alarming increase in life‐threatening heart disease for millions of cancer survivors. Therefore, developing new cardio‐oncology drugs to protect heart during and after chemotherapy is an immediate critical need. Although literature indicate that Angiotensin II type 2 receptor AT2R attenuates cardiac damage, to date there are no AT2R agonists that are used in clinic to treat heart disease. NP‐6A4 is an AT2R peptide agonist that has recently received orphan drug designation for pediatric cardiomyopathy from the FDA. Our previous studies indicated that NP‐6A4 treatment (1.8mg/kg/day) could improve cardiac function and attenuate cardiomyopathy in diabetic rats and protect human cardiovascular cells from acute nutrient stress. We hypothesized that since AT2R is a regulator of cell growth, NP‐ 6A4‐AT2R signaling will attenuate breast cancer cell growth. Here we report NP‐6A4 treatment of triple negative breast cancer cells (MDA‐MB‐231) and estrogen positive breast cancer cells (MCF‐7) resulted in significant (p<0.05) suppression of cell index (as determined by real time cell analyzer), and survival (as determined by MTS assay), albeit the underlying mechanisms were different. NP‐6A4 treatment of MCF‐7 cells augmented Tamoxifen‐induced inhibition of cell growth (p<0.05), and suppressed proliferation marker Ki67 (20%) and phosphokinases CREB (32%), Jun N‐terminal kinase (JNK) (51%) and Erk1/2 (41%). In MDA‐MB‐231 cells, NP‐6A4 treatment caused increase in apoptotic marker Caspase 3 (2.3‐fold increase), but suppressed its inhibitor phosphokinase p38 (37%) (p<0.05), and also suppressed phosphokinases CREB (30%), JNK (51%) and Erk1/2 (33%). However, doxorubicin (anthracycline)‐induced cell death was not reversed by NP‐6A4. NP‐6A4 treatment increased different tumor suppressors: ATIP 1 mRNA in MCF‐7 and ATIP‐3 mRNA in MDA‐MB‐231 (p<0.05). These data suggest that NP‐6A4 differentially regulates human breast cancer cell growth and has high potential as a synergistic cardio‐oncology drug for breast cancer treatment.Support or Funding InformationThis work was supported by NIH grants: 1R01HL118376‐01 and 1R01HL138988‐01A1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.