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Resveratrol potentiates the in vitro and in vivo anti-tumoral effects of curcumin in head and neck carcinomas.

ABSTRACT: The survival rate of head and neck squamous cell carcinomas (HNSCC) patients has not considerably changed over the last two decades. Polyphenols inhibit the growth of cancer cells. We determined whether the combination of Resveratrol (RES) and Curcumin (CUR) enhanced their in vitro and in vivo antitumor activities on HNSCC cell lines compared to the single compounds. We provide evidence that RES potentiated the apoptotic effect and reduced the IC50 of CUR on HNSCC cell lines. The model of compounds interaction indicated the onset of an additive effect of the two compounds compared to the single treatment after decrease of their concentrations. RES+CUR compared to CUR increased the PARP-1 cleavage, the Bax/Bcl-2 ratio, the inhibition of ERK1 and ERK2 phosphorylation, and the expression of LC3 II simultaneously with the formation of autophagic vacuoles. RES and CUR induced cytoplasmic NF-?B accumulation. RES+CUR administrations were safe in BALB/c mice and reduced the growth of transplanted salivary gland cancer cells (SALTO) more efficiently than CUR. Overall, combinations of CUR and RES was more effective in inhibiting in vivo and in vitro cancer growth than the treatment with CUR. Additional studies will be needed to define the therapeutic potential of these compounds in combination.

SUBMITTER: Masuelli L

PROVIDER: S-EPMC4279407 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Resveratrol potentiates the in vitro and in vivo anti-tumoral effects of curcumin in head and neck carcinomas.

Masuelli Laura L Di Stefano Enrica E Fantini Massimo M Mattera Rosanna R Benvenuto Monica M Marzocchella Laura L Sacchetti Pamela P Focaccetti Chiara C Bernardini Roberta R Tresoldi Ilaria I Izzi Valerio V Mattei Maurizio M Frajese Giovanni Vanni GV Lista Florigio F Modesti Andrea A Bei Roberto R

Oncotarget 20141101 21

The survival rate of head and neck squamous cell carcinomas (HNSCC) patients has not considerably changed over the last two decades. Polyphenols inhibit the growth of cancer cells. We determined whether the combination of Resveratrol (RES) and Curcumin (CUR) enhanced their in vitro and in vivo antitumor activities on HNSCC cell lines compared to the single compounds. We provide evidence that RES potentiated the apoptotic effect and reduced the IC50 of CUR on HNSCC cell lines. The model of compou ...[more]

PMID: 25296980

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Project description:BackgroundMechanisms by which Smac mimetics (SMs) interact with proteasome inhibitors (e.g., bortezomib) are largely unknown, particularly in multiple myeloma (MM), a disease in which bortezomib represents a mainstay of therapy.MethodsInteractions between the clinically relevant IAP (inhibitor of apoptosis protein) antagonist birinapant (TL32711) and the proteasome inhibitor bortezomib were investigated in multiple myeloma (MM) cell lines and primary cells, as well as in vivo models. Induction of apoptosis and changes in gene and protein expression were monitored using MM cell lines and confirmed in primary MM cell populations. Genetically modified cells (e.g., exhibiting shRNA knockdown or ectopic expression) were employed to evaluate the functional significance of birinapant/bortezomib-induced changes in protein levels. A MM xenograft model was used to evaluate the in vivo activity of the birinapant/bortezomib regimen.ResultsBirinapant and bortezomib synergistically induced apoptosis in diverse cell lines, including bortezomib-resistant cells (PS-R). The regimen robustly downregulated cIAP1/2 but not the canonical NF-κB pathway, reflected by p65 phosphorylation and nuclear accumulation. In contrast, the bortezomib/birinapant regimen upregulated TRAF3, downregulated TRAF2, and diminished p52 processing and BCL-XL expression, consistent with disruption of the non-canonical NF-κB pathway. TRAF3 knockdown, ectopic TRAF2, or BCL-XL expression significantly diminished birinapant/bortezomib toxicity. The regimen sharply increased extrinsic apoptotic pathway activation, and cells expressing dominant-negative FADD or caspase-8 displayed markedly reduced birinapant/bortezomib sensitivity. Primary CD138+ (n = 43) and primitive MM populations (CD138-/19+/20+/27+; n = 31) but not normal CD34+ cells exhibited significantly enhanced toxicity with combined treatment (P < 0.0001). The regimen was also fully active in the presence of HS-5 stromal cells or growth factors (e.g., IL-6 and VEGF). Finally, the regimen was well tolerated and significantly increased survival (P < 0.05 and P < 0.001) compared to single agents in a MM xenograft model. Combined treatment also downregulated cIAP1/2 and p52 while increasing PARP cleavage in MM cells in vivo.ConclusionsOur data suggest that birinapant and bortezomib interact synergistically in MM cells, including those resistant to bortezomib, through inactivation of the non-canonical NF-κB and activation of the extrinsic apoptotic pathway both in vitro and in vivo. They also argue that a strategy combining cIAP antagonists and proteasome inhibitors warrants attention in MM.

Dataset Information

Resveratrol potentiates the in vitro and in vivo anti-tumoral effects of curcumin in head and neck carcinomas.

Publications

Resveratrol potentiates the in vitro and in vivo anti-tumoral effects of curcumin in head and neck carcinomas.

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