Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids

Abstract

Peptaibols, by disturbing the permeability of phospholipid membranes, can overcome anticancer drug resistance, but their natural hydrophobicity hampers their administration. By a green peptide synthesis protocol, we produced two water-soluble analogs of the peptaibol trichogin GA IV, termed K6-Lol and K6-NH2. To reduce production costs, we successfully explored the possibility of changing the naturally occurring 1,2-aminoalcohol leucinol to a C-terminal amide. Peptaibol activity was evaluated in ovarian cancer (OvCa) and Hodgkin lymphoma (HL) cell lines. Peptaibols exerted comparable cytotoxic effects in cancer cell lines that were sensitive—and had acquired resistance—to cisplatin and doxorubicin, as well as in the extrinsic-drug-resistant OvCa 3-dimensional spheroids. Peptaibols, rapidly taken up by tumor cells, deeply penetrated and killed OvCa-spheroids. They led to cell membrane permeabilization and phosphatidylserine exposure and were taken up faster by cancer cells than normal cells. They were resistant to proteolysis and maintained a stable helical structure in the presence of cancer cells. In conclusion, these promising results strongly point out the need for further preclinical evaluation of our peptaibols as new anticancer agents.

Development of Breast Cancer Spheroids to Evaluate Cytotoxic Response to an Anticancer Peptide

“…Fewer apoptotic cells were visualized in spheroids treated with vCPP2319, when compared with controls, which means that cells were already compromised or were already dead at the time of detection (Figure 5). A decrease in potency has been reported already in other studies [60][61][62]. Based on these findings, we suggest that anticancer drug candidates should be tested in spheroids to properly characterize their efficacy.…”

Exploring Peptaibol’s Profile, Antifungal, and Antitumor Activity of Emericellipsin A of Emericellopsis Species from Soda and Saline Soils

“…Many authors have described peptaibols with antifungal activity, but most of them possessed activity against plant pathogens and fungi and are currently receiving significant attention because of their applications as bio fungicides [ 19 , 25 ]. In recent years, a few studies have obtained the activity of peptaibols against clinical pathogenic fungi and cancer lines [ 5 , 11 , 14 , 25 , 31 , 32 , 33 , 34 ].…”

“…Some peptaibols have also been proposed as antitumor molecules [ 31 , 32 , 33 , 46 ]. Indeed, they display selective cytotoxicity toward cancer cells, which has been ascribed to the different composition and physical properties of the cancer cell membrane relative to healthy cells [ 20 , 25 , 31 , 33 , 46 , 47 ].…”

“…Some peptaibols have also been proposed as antitumor molecules [ 31 , 32 , 33 , 46 ]. Indeed, they display selective cytotoxicity toward cancer cells, which has been ascribed to the different composition and physical properties of the cancer cell membrane relative to healthy cells [ 20 , 25 , 31 , 33 , 46 , 47 ]. Reinvestigation of the well-known peptaibol producer Trichoderma arundinaceum strain MSX70741 to discover new anticancer compounds led to the isolation of three new peptaibols with antitumor activity.…”

Design, Synthesis, and Preclinical Activity in Ovarian Cancer Models of New Phosphanegold(I)-N-heterocyclic Carbene Complexes

“…Spheroid volumes were calculated using the formula (width 2 × length × 3.14)/6. 82,83 To obtain multiple spheroids, 5.0 × 10 4 /mL SKOV3 cells were seeded in nonadherent conditions on poly-HEMA coated wells for 4 days. After drug treatment viable cells were evaluated using PrestoBlue cell viability reagent (Thermo Fisher Scientific, Frederick, MD, USA) or alternatively trypsinized to a single cell suspension for further analysis.…”