Abstract
Pancreatic cancer has a poor prognosis attributed in part to immune suppression and deactivation of natural killer (NK) cells. Curcuminoids have a potential for improving the therapy of pancreatic cancer given promising results in cancer models and a clinical trial, but their oral absorption is limited. Our objective in this study is to show curcuminoid anti-oncogenic effects alone and together with human NK cells. We tested curcuminoids in an emulsion of ω-3 fatty acids and anti-oxidants (“Smartfish”) regarding their direct cytocidal effect and enhancement of the cytocidal activity of NK cells in pancreatic ductal adenocarcinoma (PDAC) cells (Mia Paca 2 and L3.6). Curcuminoids (at ≥10 μM) with ω-3 fatty acids and anti-oxidants or with the lipidic mediator resolvin D1 (RvD1) (26 nM) induced high caspase-3 activity in PDAC cells. Importantly, curcuminoids with ω-3 fatty acids and anti-oxidants or with RvD1 significantly potentiated NK cell cytocidal function and protected them against degradation. In a co-culture of cancer cells with NK cells, interferon-γ (IFN-γ) production by NK cells was not altered by ω-3 fatty acids with anti-oxidants or by RvD1 but was inhibited by curcuminoids. The inhibition was not eliminated by ω-3 fatty acids or RvD1 but was relieved by removing curcuminoids after adding NK cells. In conclusion, curcuminoids with ω-3 fatty acids and anti-oxidants or with RvD1 have increased cytotoxic activity on PDAC cells alone and with NK cells. The effects of curcuminoids with ω-3 fatty acids and anti-oxidants on pancreatic cancer will be investigated in a mouse model with humanized immune system.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths in the United States with an overall survival of less than 1 year and based on current statistics is predictedCurcumin and ω-3 in pancreatic cancer to become the 2nd leading cause of cancer-related deaths by 2020 (American Cancer Society, 2012)
As shown in integrated optical density (IOD) of red per cell, caspase-3 expression was not observed in untreated Mia Paca2 (MP2) cells (IOD Red/Cell = 21.29), but was seen at a low level in MP2 cells treated with ω-3 and anti-oxidants (IOD Red/Cell = 49.87), and at a high level in MP-2 cells treated with curcuminoids or resolvin D1 (RvD1) emulsified in ω-3 with anti-oxidants (IOD Red/Cell = 257.01 and 227.55, respectively)
We evaluated the induction of the apoptosis executioner caspase3 by curcuminoids and ω-3 or the lipid mediator RvD1 in pancreatic ductal adenocarcinoma (PDAC) cells as (a) direct effects, and (b) combined effects with natural killer (NK) cells
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths in the United States with an overall survival of less than 1 year and based on current statistics is predictedCurcumin and ω-3 in pancreatic cancer to become the 2nd leading cause of cancer-related deaths by 2020 (American Cancer Society, 2012). Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths in the United States with an overall survival of less than 1 year and based on current statistics is predicted. Chemotherapy has been less successful in PDAC in comparison to other cancers. The immune system is modulated by cancer to inhibit the cytotoxic function of natural killer (NK) cells and CD8 T cells through activation of regulatory T cells, myeloid derived suppressor (MDSC) cells, tumor associated macrophages and fibroblasts. The immune therapies of pancreatic cancer using vaccination with cancer proteins and inactivated allogeneic cancer cells and adoptive cell therapy using cytotoxic T cells have not produced clear results in short-term trials (Sideras et al, 2013).
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