Piscidin-1 Induces Apoptosis via Mitochondrial Reactive Oxygen Species-Regulated Mitochondrial Dysfunction in Human Osteosarcoma Cells

Abstract

Osteosarcoma (OSA) is the most common type of cancer that originates in the bone and usually occurs in young children. OSA patients were treated with neoadjuvant chemotherapy and surgery, and the results were disappointing. Marine antimicrobial peptides (AMPs) have been the focus of antibiotic research because they are resistant to pathogen infection. Piscidin-1 is an AMP from the hybrid striped bass (Morone saxatilis × M. chrysops) and has approximately 22 amino acids. Research has shown that piscidin-1 can inhibit bacterial infections and has antinociception and anti-cancer properties; however, the regulatory effects of piscidin-1 on mitochondrial dysfunction in cancer cells are still unknown. We aimed to identify the effects of piscidin-1 on mitochondrial reactive oxygen species (mtROS) and apoptosis in OSA cells. Our analyses indicated that piscidin-1 has more cytotoxic effects against OSA cells than against lung and ovarian cancer cells; however, it has no effect on non-cancer cells. Piscidin-1 induces apoptosis in OSA cells, regulates mtROS, reduces mitochondrial antioxidant manganese superoxide dismutase and mitochondrial transmembrane potential, and decreases adenosine 5′-triphosphate production, thus leading to mitochondrial dysfunction and apoptosis. The mitochondrial antioxidant, mitoTempo, reduces the apoptosis induced by piscidin-1. Results suggest that piscidin-1 has potential for use in OSA treatment. When immature bones in the body become cancerous, it is called osteosarcoma (OSA), which is the most common type of bone cancer 1 , and is found at the end of long bones, usually around the knee 2. Clinically diagnosed OSA patients are usually younger than 25 years of age and the cause of OSA is unclear 3. Current treatments for OSA include neo-adjuvant chemotherapy, followed by surgery and post-operative treatment 4. The 5-year survival rate

Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption

“…The Cu 2+ -bound peptides did not exhibit this strong level of cytotoxicity on normal MRC-5 (lung) fibroblast cells (Fig. S1 C), in agreement with the data previously obtained for apo-P1 on MRC-5, HGF-1 (gingival) and OMF (mucosal) fibroblast cells 39 , 78 . Higher selectivity of the cationic peptides for cancer cells is very likely related to different chemical conditions of their membrane environment, as explained in the introduction.…”

“…Our study focused on showing that metallation enhances the cytotoxic effects of piscidins 1 and 3 on cancer cells and explaining this effect through a detailed characterization of peptide-lipid interactions. As a next step, it will be important to determine whether the mechanism of cell death by P1 and P3 bound to Cu 2+ features apoptosis, as previously shown for apo-P1 39 , 78 . For instance, it would be insightful to use cell-based assays to determine whether the Cu 2+ -bound peptides release Cu 2+ intracellularly (e.g., acidic endosomes) resulting in enhanced ROS formation and increased apoptotic effects compared to apo-P1 used at low concentration.…”

“…With regard to cancer cells, Lin et al showed that apo-P1 exerts apoptotic effects on HT1080 cells at low concentrations while its mechanism of action is necrotic at higher doses 39 . Cheng et al more recently observed that apo-P1 also has apoptotic effects on osteosarcoma (bone) cancer cells 78 . More specifically, the peptide enhanced the formation of mitochondrial ROS, resulting in oxidative damage.…”

Neferine induces mitochondrial dysfunction to exert anti-proliferative and anti-invasive activities on retinoblastoma

“…Cheng et al. 32 reported that Piscidin-1 induced apoptosis via mitochondrial reactive oxygen species-regulated mitochondrial dysfunction in human osteosarcoma cells. 32 Nevertheless, key steps remain to be corroborated, especially those that lead to selective killing of cancer cells.…”

“…32 reported that Piscidin-1 induced apoptosis via mitochondrial reactive oxygen species-regulated mitochondrial dysfunction in human osteosarcoma cells. 32 Nevertheless, key steps remain to be corroborated, especially those that lead to selective killing of cancer cells. How to effectively use mitochondrial dysfunction and its regulatory role in cancer to kill anti-cancer cells in a heterogeneous cell population in tumors is still a promising but not yet fulfilled premise.…”