Enhanced anti-tumor activity of a new curcumin-related compound against melanoma and neuroblastoma cells

Abstract

BackgroundSharing the common neuroectodermal origin, melanoma and neuroblastoma are tumors widely diffused among adult and children, respectively. Clinical prognosis of aggressive neuroectodermal cancers remains dismal, therefore the search for novel therapies against such tumors is warranted. Curcumin is a phytochemical compound widely studied for its antioxidant, anti-inflammatory and anti-cancer properties. Recently, we have synthesized and tested in vitro various curcumin-related compounds in order to select new anti-tumor agents displaying stronger and selective growth inhibition activity on neuroectodermal tumors.ResultsIn this work, we have demonstrated that the new α,β-unsaturated ketone D6 was more effective in inhibiting tumor cells growth when compared to curcumin. Normal fibroblasts proliferation was not affected by this treatment. Clonogenic assay showed a significant dose-dependent reduction in both melanoma and neuroblastoma colony formation only after D6 treatment. TUNEL assay, Annexin-V staining, caspases activation and PARP cleavage unveiled the ability of D6 to cause tumor cell death by triggering apoptosis, similarly to curcumin, but with a stronger and quicker extent. These apoptotic features appear to be associated with loss of mitochondrial membrane potential and cytochrome c release. In vivo anti-tumor activity of curcumin and D6 was surveyed using sub-cutaneous melanoma and orthotopic neuroblastoma xenograft models. D6 treated mice exhibited significantly reduced tumor growth compared to both control and curcumin treated ones (Melanoma: D6 vs control: P < 0.001 and D6 vs curcumin P < 0.01; Neuroblastoma: D6 vs both control and curcumin: P < 0.001).ConclusionsOur data indicate D6 as a good candidate to develop new therapies against neural crest-derived tumors.

Molecular changes induced by the curcumin analogue D6 in human melanoma cells

“…The D6 compound was proved to promote apoptosis in melanoma cells through the mitochondrial intrinsic pathway [21]. In vivo assays on mouse models confirmed the potential of D6 against melanoma, showing a significant reduction of the tumour mass growth as compared to untreated control [21]. …”

“…This genomic technology is useful to dissect the molecular changes occurring inside cancer cells, and it is well documented for malignant melanoma [22,23]. In our study, the LB24Dagi (LB24) primary melanoma cell line was selected for all the analyses, because it had been previously demonstrated to be the most sensitive line to D6 treatment among tested ones [21]. Several molecular changes that can justify the antiproliferative and proapoptotic properties of D6 on melanoma cells and likely contribute to its anti-tumour effect have been here presented and discussed.…”

Phytochemicals for the Management of Melanoma

“…This has led the way for researchers to further study the structure-activity relationship of curcumin in medicinal chemistry [209, 210]. Interestingly, Pisano et al [211] recently showed that a new curcumin analog alpha,beta-unsaturated ketone D6 [(3E,3'E)-4,4'-(5,5',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-diyl)bis(but-3-en-2-one)] (Fig. 5E) was more effective at inhibiting melanoma cell growth and inducing apoptosis in vitro and in vivo when compared to curcumin [211, 212].…”

“…Interestingly, Pisano et al [211] recently showed that a new curcumin analog alpha,beta-unsaturated ketone D6 [(3E,3'E)-4,4'-(5,5',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-diyl)bis(but-3-en-2-one)] (Fig. 5E) was more effective at inhibiting melanoma cell growth and inducing apoptosis in vitro and in vivo when compared to curcumin [211, 212]. Other curcumin analogs (FLLL32 and FLLL62) (Fig.…”

Bioactive Food Components for Melanoma: An Overview

“…Recent advances in view of selecting new antitumor agents with more potent and selective growth inhibitory activity has revolutionized the synthesis and testing of several analogous "curcumin-like" compounds. For instance the compound , -unsaturated ketone D6 was shown to be more effective in inhibiting melanoma growth when compared to curcumin [44]. Synthetic curcuminoid derivatives have been analyzed in vivo to test their inhibitory role to tumor-specific angiogenesis such that in mice injected with melanoma cells an intraperitoneal administration of tetrahydro curcumin, salicyl curcumin and curcumin III reduced the number of induced tumor-directed capillaries.…”