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. 2008 Aug 15;83(7-8):293-300.
doi: 10.1016/j.lfs.2008.06.017. Epub 2008 Jun 28.

Synergistic effects of multiple natural products in pancreatic cancer cells

Zhiwei Wang  1 , Sita Desmoulin, Sanjeev Banerjee, Dejuan Kong, Yiwei Li, Rohan L Deraniyagala, James Abbruzzese, Fazlul H Sarkar
Affiliations

Synergistic effects of multiple natural products in pancreatic cancer cells

Zhiwei Wang et al. Life Sci. .

Abstract

Pancreatic cancer (PC) remains the fourth most common cause of cancer related death in the United States. Therefore, novel strategies for the prevention and treatment are urgently needed. Numerous dietary and pharmacological agents have been proposed as alternative strategies for the prevention and/or treatment of PC. Isoflavone is a prominent flavonoid found in soy products and has been proposed to be responsible for lowering the incidence of PC in Asians. Similarly, curcumin, an active ingredient of turmeric, that inhibits growth of malignant neoplasms, has a promising role in the prevention and/or treatment of PC. Here we examined whether isoflavone together with curcumin could elicit a greater inhibition of growth of PC cells than either agent alone, and also sought to determine the molecular mechanism of action. We found that the inhibition of cell growth and induction of apoptosis was significantly greater in the combination group than that could be achieved by either agent alone. These changes were associated with decreased Notch-1 expression and DNA binding activity of NF-kappaB and its target genes such as Cyclin D1, Bcl-2, and Bcl-xL. Moreover, we found that the combination of four natural agents at lower concentration was much more effective. Collectively, our results suggest that diet containing multiple natural products should be preferable over single agents for the prevention and/or treatment of PC. The superior effects of the combinatorial treatment could partly be attributed to the inhibition of constitutive activation of Notch-1 and NF-kappaB signaling pathways.

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Figures

Figure 1
Figure 1
Effect of isoflavone or curcumin on BxPC-3 and Colo-357 cell growth. Dose and time-dependent inhibition of cell growth by isoflavone and curcumin in BxPC-3 and Colo-357 PC cells. Cells were seeded in 96-well plates at 5,000 cells per well and treated with the indicated concentrations of isoflavone or curcumin for various time periods. After treatment, cell viability was determined by MTT assay. Each value represents the mean ± SD (n=6) of three independent experiments. * P<0.05, **P<0.01 compared with the control.
Figure 2
Figure 2
Effects of the combination of isoflavone (Iso) and curcumin (Cur) on cell growth of BxPC-3 and Colo-357 cells. Each value represents the mean ± SD (n=6) of three independent experiments. * P<0.05, **P<0.01 compared with the control.
Figure 3
Figure 3
Effects of isoflavone (Iso) or curcumin (Cur) alone or their combination on apoptosis of BxPC-3 and Colo-357 cells. The cells were incubated for 72 h in the absence (control) or presence of indicated concentrations of isoflavone and/or curcumin. Values represent mean ± SD of 5-6 observations. * P<0.05, **P<0.01 compared with the control.
Figure 4
Figure 4
A-B, Isobologram analyses of synergy between combinations of isoflavone and curcumin in BxPC-3 cells. The cells were incubated for 72 h in the absence (control) or presence of indicated concentrations of isoflavone and/or curcumin. Data points (*) are described by concentrations (in μM) of curcumin and isoflavone reflected on x- and y-axes respectively, and are representative of three independent experiments. Combination index (CI): a quantitative measure of the degree of drug interaction. CI < 1 indicates synergism; CI > 1 indicates antagonism; CI = 1 indicates additive effect. C-D, Western blot analysis showing changes in the levels of Notch-1, Cyclin D1 and Bcl-xL as well as the levels of Bcl-2 in BxPC-3 and Colo-357 cells treated with isoflavone, curcumin, or their combination for 72 h. β-actin represents protein loading control.
Figure 5
Figure 5
Electrophoretic mobility shift assay (EMSA) showing the DNA binding activity of NF-κB in nuclear protein fractions from untreated (control), isoflavone-, curcumin-, or isoflavone + curcumin-treated BxPC-3 and Colo-357 cells. Super-shift assay showed that NF-κB band was shifted because of the formation of bigger complex after addition of anti- NF-κB p65 antibody. This assay confirmed the specificity of NF-κB binding to the DNA consensus sequence.
Figure 6
Figure 6
Effects of isoflavone, curcumin, resveratrol, EGCG alone, or the combination of four compounds on cell growth of pancreatic cancer BxPC-3 cells. Each value represents the mean ± SD (n=6) of three independent experiments. * P<0.05, **P<0.01 compared with the control.
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