We studied combinatorial interactions of two phytochemicals, curcumin and silymarin, in their action against cancer cell proliferation. Curcumin is the major component of the spice turmeric. Silymarin is a bioactive component of milk thistle used as a protective supplement against liver disease. We studied antiproliferative effects of curcumin alone, silymarin alone and combinations of curcumin and silymarin using colon cancer cell lines (DLD-1, HCT116, LoVo). Curcumin inhibited colon cancer cell proliferation in a concentration-dependent manner, whereas silymarin showed significant inhibition only at the highest concentrations assessed. We found synergistic effects when colon cancer cells were treated with curcumin and silymarin together. The combination treatment led to inhibition of colon cancer cell proliferation and increased apoptosis compared to single compound treated cells. Combination treated cells exhibited marked cell rounding and membrane blebbing of apoptotic cells. Curcumin treated cells showed 3-fold more caspase3/7 activity whereas combination treated cells showed 5-fold more activity compared to control and silymarin treated cells. When DLD-1 cells were pre-exposed to curcumin, followed by treatment with silymarin, the cells underwent a high amount of cell death. The pre-exposure studies indicated curcumin sensitization of silymarin effect. Our results indicate that combinatorial treatments using phytochemicals are effective against colorectal cancer.

The B‐cell‐specific Moloney murine leukemia virus integration site 1 (BMI1) locus encodes a 37‐kD protein that is a key regulatory component of the polycomb regulatory complex 1 (PRC1). When overexpressed in various cancer types, the BMI1 protein induces cell growth and promotes tumor growth in vitro and in vivo. Curcumin, a major phytochemical in turmeric (Curcuma longa), inhibits the proliferation and survival of many types of cancer cells, both in vitro and in vivo, and has been reported to reduce BMI1 expression in breast cancer cells. In this study, effects of curcumin and two analogs (bisdemethoxycurcumin and dimethoxycurcumin) on BMI1 expression were evaluated in DLD‐1 colorectal cancer cells. Bisdemethoxycurcumin (BDMC) is naturally occurring in turmeric, whereas dimethoxycurcumin (DMC) is a synthetic analog of curcumin. All three compounds reduced cell survival, but only the natural compound downregulated BMI1 protein expression; curcumin significantly reduced BMI1 levels more than bisdemethoxycurcumin and dimethoxycurcumin. In addition, curcumin and BDMC inhibit survival of the DLD‐1 colorectal cancer cells by inducing apoptosis, whereas DMC inhibits survival by a mechanism other than apoptosis.

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Phytochemicals are plant‐based, non‐toxic compounds that produce health benefits. Curcumin, a major phytochemical in turmeric, inhibits the proliferation of many types of cancer cells, both in vitro and in vivo. Phytochemicals subvert carcinogenesis by modifying methylation patterns normally maintained by cancer cells. This methylation modification mechanism indirectly influences the regulatory microRNA that maintains normal cell division. Earlier, we identified that curcumin exerts an antiproliferative effect on DLD‐1 colon cancer cells in a dose dependent manner. After 48‐hour treatment of DLD‐1 cells with curcumin, expression level of tumor suppressor gene, RASSF1A, and microRNA‐15a (miR‐15a) was evaluated. Normally, expression levels of both RASSF1A and miR‐15a were suppressed in DLD‐1 cells; however, upon curcumin treatment, expression levels of RASSF1A and miR‐15a were higher than those in vehicle‐treated controls. Also, the miR‐15a target, BMI1, was suppressed in curcumin‐treated cells. In summary, curcumin exerted an antiproliferative effect against colon cancer cells, possibly by an epigenetic mechanism.KV and RD were supported by the DeNardo Foundation Fellowship.

Phytochemicals are natural plant‐derived products that show preventative and therapeutic properties against a wide range of human diseases. Studies comparing the effects of Western and Eastern diets on disease outcome have shown that consumption of a diet rich in these phytochemicals proves effective in inhibiting colon cancer. Curcumin, the predominant hydrophobic polyphenolic compound that is isolated from the rhizomes of Curcuma longa, has attracted a lot of attention due to its diverse applications in traditional medicines as a potent anti‐inflammatory, antioxidant, antiangiogenic and anticancer agent. Despite its promising chemotherapeutic activity, preclinical and clinical studies of curcumin highlight its narrow in vivo therapeutic application due to its instability and limited bioavailability in human physiological conditions. For these reasons, we compared the chemotherapeutic effects of three curcumin derivatives, dimethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin, that studies have shown to have increased bioavailability and antiproliferative effects on various cancer cell lines, versus curcumin by measuring their antiproliferative effects on the DLD‐1 colon cancer cell line. The results showed that while bisdemethoxycurcumin (IC50 = 10 μM) showed similar effects and tetrahydrocurcumin (IC50 = 50 μM) showed less potent antiproliferative effects than curcumin, dimethoxycurcumin showed 6‐fold increased potency (IC50 = 2 μM) compared to curcumin. In previous experimental studies on curcumin we observed that the antiproliferative effects of the phytochemical were enhanced in combination with silymarin, the bioactive component of milk thistle. Given this promising synergistic interaction and given the range of results displayed in our current study of the curcumin derivatives, our future experiment will be focused on the comparative studies of the potential synergistic interactions of dimethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin with silymarin.Support or Funding InformationNK and TA are supported by the DeNardo Education and Research Foundation Fellowship.