Combining gamma-tocopherol and aspirin synergistically suppresses colitis-associated colon tumorigenesis and modulates the gut microbiota in mice, and inhibits the growth of human colon cancer cells

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Abstract

Despite being shown to be effective for chemoprevention of colorectal cancer, aspirin has limitations including adverse effects and inability to block colitis-associated colon cancer (CAC). γ-Tocopherol (γT), a vitamin E form, has been reported to mitigate experimental colitis and CAC, prolong the anti-inflammatory activity of aspirin and alleviate aspirin-induced adverse effect. We therefore hypothesize that combining γT and aspirin is better than either compound singly for suppressing CAC. This hypothesis was tested in the murine azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model and with human HCT116 colon cancer cells. Compared to the control, combining aspirin (250 ppm) and γT (500 ppm) but not either compound alone significantly reduced AOM/DSS-induced tumor area and multiplicity of large-size tumors by 60% and 50%, respectively. Meanwhile, γT mitigated aspirin-promoted inflammation and stomach lesions in mice. Moreover, the combination appeared to cause favorable changes of gut microbiota compared to the control and synergistically suppressed the growth of HCT116 cells. Our study demonstrates that combining aspirin and γT improves anticancer effects and counteracts side effects compared to aspirin and may therefore be a novel combinatory chemopreventive agent against CAC.

Section snippets

Funding

This work was in part supported by Purdue Research Foundation, USDA Hatch 1022869 and a pilot grant from the Purdue University Center for Cancer Research, NIH grant P30CA023168. This publication was made possible with support from the Purdue Institute of Inflammation, Immunology and Infectious Disease (PI4D).

Reagents and diets

γT (95–99%) was from Sigma (St. Louis, MO) or Yasoo Health Inc (Johnson City, TN). Azoxymethane (AOM) was obtained from Sigma and dextran sodium sulfate (DSS, MW 36,000–50,000) was from MP Biochemicals (Solon, Ohio). Aspirin, dimethyl sulfoxide (DMSO), [3-(4,5)-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and all other chemicals were from Sigma.

In the animal study, supplement diets were made by adding aspirin (0.025% diet = 250 ppm), or γT (0.05% = 500 ppm) or their combination

Combining γT and aspirin, but not either compound alone, decreased AOM/DSS-induced tumorigenesis

As designed in Fig. 1A, we examined the effect of dietary supplementation of aspirin, γT and their combination on AOM/DSS-induced colon tumorigenesis in male Balb/c mice. Since supplementations started a week after injection of AOM, this design allowed us to assess the effect on tumor development after induction of carcinogenesis. None of the supplementation had any impact on body weight compared to the control diet (Fig. 1B). Like our previous observations (Jiang et al., 2013), AOM/DSS

Discussion

Although many studies support aspirin for prevention of sporadic CRC (Chan et al., 2012; Flossmann and Rothwell, 2007; Maresso et al., 2015), the effect of aspirin on CAC has been controversial. In particular, epidemiological data do not support the use of aspirin for preventing IBDs-associated colon cancer (Burr et al., 2016). Aspirin also fails to block CAC in rodents (Chiu et al., 2000; Guo et al., 2017; Tian et al., 2011), except for one study (Guo et al., 2016), but the same team did not

Credit author statement

Kilia Liu: investigation, data curation, writing original draft preparation; Qianyu Wang: formal analysis; Cindy Nakatsu: supervision, writing, review and editing; Yava Jones-Hall: data curation, writing, review and editing; Qing Jiang: Conceptualization, administration, funding acquisition, supervision, writing and editing.

Declaration of competing interest

None.

Acknowledgement

The authors thank Yiying Zhao for her help with gut microbiota and statistical analyses.

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