The molecular mechanism of action of aspirin, curcumin and sulforaphane combinations in the chemoprevention of pancreatic cancer

Abstract

Pancreatic cancer ranks as the fourth most deadly form of cancer in the United States with ~37,000 deaths each year. The present study evaluated the chemopreventive potential of a combination of aspirin (ASP), curcumin (CUR) and sulforaphane (SFN) in low doses to human pancreatic cancer cells, MIA PaCa-2 and Panc-1. Results demonstrated that low doses of ASP (1 mM), CUR (10 μM) and SFN (5 μM) (ACS) combination reduced cell viability by ~70% (P<0.001), and also induced cell apoptosis by ~51% (P<0.001) accompanied by activation of caspase-3 and Poly(ADP-ribose) polymerase (PARP) proteins. The NF-κB DNA binding activity was inhibited by ~45% (P<0.01) and ~75% (P<0.001) in MIA PaCa-2 and Panc-1 cells, respectively. Mechanistic studies revealed that ACS promoted increase expression of phospho extracellular signal-regulated kinase 1/2 (P-ERK1/2), c-Jun, p38 MAPK and p53 proteins. Furthermore, the cells pretreated with U0126 (ERK1/2 inhibitor) partially abolished the effect of ACS on cell viability. Data from this study demonstrate that a low-dose ACS combination inhibits cell growth by inducing cell apoptosis, and proposes sustained activation of the ERK1/2 signaling pathway as one of the possible mechanisms.

Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature

“…A combination of Aspirin, Curcumin and Sulforaphane synergistically reduces cell viability by 70% and significantly induce apoptosis by 51% through the inhibition of NF-κB and activation of EERK1/2 [88]. The nanoencapsulated (solid-lipid nanoparticles) combination of all 3 drugs reduces tumour incidences by 75% and the cell proliferation by 72.8% with low toxicity [116].…”

“…Sulforaphane is an isothiocyanate that induces apoptosis and cell cycle arrest, reduces cell growth and suppresses NF-κB [66,88]. Benzyl isothiocyanate induction of apoptosis and cell cycle arrest at the G2/M phase, and phenethyl isothiocyanate are also chemopreventive agents in cancer cells and xenograft models [66,75].…”

Combination of Chemopreventive Agents in Nanoparticles for Cancer Prevention

“…The induction of phase II xenobiotic-metabolizing enzymes, antioxidant enzymes, and other detoxification enzymes has been shown to be a major mechanism of action for sulforaphane; however, other mechanisms have also been suggested (17). In the study by Grandhi and colleagues (11), it is not known whether these three agents produce a synergistic or additive effect when used together, even though the mechanisms of their actions have been studied previously in pancreatic cell lines by the same research group (18,19). It would be a challenge in future studies to elucidate the specific targets or pathways that are affected by these agents, as well as the mechanisms by which the synergy is generated.…”

Mechanisms of the Anticancer Effects of Isothiocyanates

“…Combination of SFN and 3,3 0 -diindolylmethane enhanced the cell cycle arrest in colon cancer cells synergistically [160]. Combination of curcumin and ITCs showed remarkable decrease in the levels of inflammatory markers [161,162]. Epigallocatechin gallate, a potent anticancer compound from green tea, exhibited significant chemopreventive effects in transgenic model of prostate cancer when combined with SFN [163].…”