The tumor stroma acts as a barrier that limits the efficacy of systemically administered oncolytic viruses (OV). We previously demonstrated that stromal-selective, retargeted oncolytic measles viruses (MVs) delay in vivo tumor progression. To further characterize the contribution of stromal targeting to MV's overall in vivo efficacy in an experimental cancer model, a dual targeted oncolytic measles virus (MV-CD46-muPA) able to simultaneously infect murine stromal (via murine uPAR) and human cancer (via CD46) cells was developed. MV-CD46-muPA infected, replicated, and induced cytotoxicity in both murine and human cancer cells. Viral infection was successfully transferred from stromal to tumor cells in vitro, leading to tumor cell oncolysis. Systemic administration of MV-CD46-muPA led to improved antitumor effects in colon (HT-29) cancer xenografts compared to vehicle or CD46 only targeted MVs. These effects were associated with improved tumor viral deposition, increased apoptosis, and decreases in murine stromal endothelial cells and fibroblasts. MV-CD46-muPA modulated cell cycle, survival, proliferation, and metabolic pathways, as determined by functional proteomic analysis of treated tumors. The above findings further validate the concept that dual stromal and tumor cell viral targeting enhances the therapeutic effects of systemically administered OVs and support further preclinical and clinical development of stromal directed virotherapies.

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Results of epidemiological studies show that people who consume diets rich in phytochemicals (such as individuals living in India) have lower rates of colorectal cancer. Occasional exposure of colonic cells to a single phytochemical may be insignificant in inhibiting growth of cancer cells, whereas regular and repeated exposure of colonic cells to phytochemicals alone or in combination with other phytochemicals may be efficacious in preventing colon cancer. Combinations of phytochemicals may provide additive or synergistic effects and could be a potent way to prevent or eliminate colon cancer initiation and/or progression. The focus of this project was to determine the effect of phytochemicals alone or in combination on cancer cell proliferation. Of interest were curcumin, a phytochemical in turmeric, and kaempferol, a phytochemical in many vegetables, fruits and beans, since they both have been reported to have anti‐cancer potential. Antiproliferative effects of curcumin and kaempferol were assessed using the DLD‐1 colon cancer cell line of epithelial origin. Initial findings indicated that both phytochemicals inhibited proliferation of DLD‐1 cells to varying extents. In particular, curcumin inhibited DLD‐1 proliferation at relatively low concentrations while kaempferol showed a significant antiproliferative effect only at high concentrations. When the concentration of curcumin was kept constant at 12.5 μM (IC50) and concentration of kaempferol was varied, a synergistic anti‐proliferative effect was observed. In fact, even the lowest concentrations of kaempferol combined with curcumin significantly inhibited colon cancer cell proliferation. Results of this study suggest that a combination of curcumin and kaempferol has significant inhibitory effects on proliferation of colon cancer cells.Support or Funding InformationFinancial support for AK, NK and TA was received from the DeNardo Education and Research Foundation.

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.