Nanoliposomal delivery of cytosolic phospholipase A2 inhibitor arachidonyl trimethyl ketone for melanoma treatment

Abstract

Drug resistance and toxicity are major limitations of cancer treatment and frequently occurs during melanoma therapy. Nanotechnology can decrease drug resistance by improving drug delivery, with limited toxicity. This study details the development of nanoparticles containing arachidonyl trifluoromethyl ketone (ATK), a cytosolic phospholipase A inhibitor, which can inhibit multiple key pathways responsible for the development of recurrent resistant disease. Free ATK is toxic, limiting its efficacy as a therapeutic agent. Hence, a novel nanoliposomal delivery system called NanoATK was developed, which loads 61.7% of the compound and was stable at 4C for 12 weeks. The formulation decreased toxicity-enabling administration of higher doses, which was more effective at inhibiting melanoma cell growth compared to free-ATK. Mechanistically, NanoATK decreased cellular proliferation and triggered apoptosis to inhibit melanoma xenograft tumor growth without affecting animal weight. Functionally, it inhibited the cPLA, AKT, and STAT3 pathways. Our results suggest the successful preclinical development of a unique nanoliposomal formulation containing ATK for the treatment of melanoma.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…1, AACOCF 3 , X I (50) 0.036) is the first GIVA cPLA 2 inhibitor reported in 1993 [41], and, although not potent and selective inhibitor, it has been widely used to study the role of this enzyme in cells and in animals. A novel nanoliposomal delivery system of inhibitor AACOCF 3 was developed for melanoma treatment [42].This system, called NanoATK, loaded 61.7% of the inhibitor and was stable at 4°C for 12 weeks. The formulation decreased toxicity-enabling administration of higher doses, which was more effective at killing melanoma cells compared to free AACOCF 3 .…”

Salubrinal in Combination With 4E1RCat Synergistically Impairs Melanoma Development by Disrupting the Protein Synthetic Machinery

“…At the end of tumorigenicity assessment, blood was collected from each euthanized animal in a serum separator tube with lithium heparin (BD Microtainer) following cardiac puncture, and subjected to a routine available panel for assessing major organ-related toxicity (24,25,32,33). Levels of GLU (Glucose), BUN (Blood urea nitrogen), CREA (Creatinine), CAL (Calcium), TPR (Total Protein), ALB (Albumin), GLB (Globulin), ALT (Alanine aminotransferase), ALKP (Alkaline phosphatase), TBIL (Total bilirubin), and AMY (Amylase) were assessed as a part of the panel.…”

Emergent Nanotechnological Strategies for Systemic Chemotherapy against Melanoma

“…The development of successful drug candidates begins with the understanding of the disease and the identification of putative therapeutic targets, leading to optimized drug-target interactions. Several targets have been associated to melanoma pathogenesis, such as tyrosinase [47,48,49], aquaporin-3 (AQP3) [50,51], folate receptor (FR) [52], integrin αvβ3 [53], cyclooxygenase-2 [54], STAT3 [54], protein phosphatase 1 [55], cytosolic phospholipase A 2 [56], melanocotin-1 receptor [57], topoisomerase 1 [58], prolyl isomerase Pin1 [59] and actin microfilaments [60]. The use of nanotechnological tools for the modulation of these therapeutic targets will be addressed in this manuscript.…”

“…Moreover, liposomal C6 did not present cytotoxicity towards normal melanocytes, suggesting its selectivity to melanoma cells [55]. In the work of Gowda and collaborators [56], PEGylated liposomes encapsulating arachidonyl trifluoromethyl ketone (ATK) (Figure 12) were studied. ATK is a cytosolic phospholipase A 2 inhibitor (Table 3, C11) proved to inhibit multiple key pathways involved in recurrent resistant melanoma, as indicated in Table 4 (F9) and Table 5 (F6).…”

“…In addition, liposomal ATK was 2 times less toxic to normal control cells compared to melanoma cell lines. In a xenograft melanoma model, nanoformulated ATK showed a dose-dependent reduction of melanoma tumor growth, with a maximum therapeutic efficacy at 30 and 40 mg/kg body weight, with no detectable toxic side effects [56].…”