Projects

Cancer Progression and Metastasis

Breast, prostate, lung and colorectal cancers account for more than 50% of newly diagnosed cancers every year, and it is estimated that these cancers will be responsible for more than 280,000 cancer deaths in the United States in 2007. The major reason for such a high mortality from these cancers is the highly invasive behavior of the cancer cells, which usually results in cancer progression and metastasis. Metastasis is the result of several interdependent processes, including cell proliferation; angiogenesis; and cell adhesion, migration, and invasion into surrounding tissue. Although these are normal physiological processes, in cancer metastasis they are the consequences of a disrupted intracellular signaling network, which transmits aberrant signals. As recently demonstrated, dietary chemopreventive agents can modulate these intracellular signaling pathways, interrupting the carcinogenic process. Therefore, naturally occurring dietary substances can be used as chemopreventive agents to slow, block, or reverse cancer metastasis. Some of the signaling molecules and/or pathways have been identified as constitutively active (by mechanisms involving overexpression of specific molecules or by autocrine/paracrine activation) and therefore are responsible for the aggressive phenotype and metastasis of many cancers, including breast, prostate and colon cancers.

Sliva D. Suppression of cancer invasiveness by dietary compounds. Mini Rev Med Chem. in press, 2008.

Ganoderma Lucidum

Ganoderma lucidum, a popular medicinal mushroom, has been used as a home remedy in traditional Chinese medicine (TCM) in many Asian countries during the past two millennia. The regular consumption of G. lucidum in the form of tea or mushroom powder was believed to preserve human vitality and promote longevity. G. lucidum also has been used for the prevention and treatment of a variety of diseases including cancer. Western medicine has recently begun to accept natural products from TCM, and the popularity of herbal therapies for the treatment of cancer has been increasing in the United States. Scientific studies elucidating the underlying mechanisms and validating their biological effects could help justify the use of these natural products as alternative or adjuvant cancer therapies. The anticancer effects of G. lucidum are associated with triterpenes, polysaccharides and, or immunomodulatory proteins, through mechanisms involving the inhibition of DNA polymerase, inhibition of post-translational modification of the Ras oncoprotein, or the stimulation of cytokine production. Furthermore, G. lucidum: (i) inhibits proliferation and invasive behavior of breast and prostate cancer cells through by down-regulating the expression of cyclin-D1 and suppressing the secretion of urokinase-plasminogen activator (uPA); (ii) inhibits growth and induces apoptosis of breast and prostate cancer cells by up-regulating the expression of p21 and Bax; (iii) inhibits the growth of hepatoma cells by suppressing protein kinase C; (iv) induces apoptosis of colon cancer cells by increasing the activity of caspase-3; (v) suppresses angiogenesis by inhibiting the secretion of vascular endothelial growth factor (VEGF) and by transforming growth factor-β1 (TGF-β1) from prostate cancer cells.

Sliva D. Ganoderma lucidum in cancer research. Leuk Res. 2006 Jul;30(7):767-8.

Phellinus Linteus

The antitumor activity of the medicinal mushroom, Phellinus linteus (PL), is known to occur through stimulation of the immune system or the induction of apoptosis. However, until recently the molecular mechanisms responsible for inhibiting the invasive behavior of cancer cells was not understood. We have now demonstrated that PL inhibits proliferation (anchorage-dependent growth) as well as colony formation (anchorage-independent growth) of highly invasive human breast cancer cells. Growth inhibition of MDA-MB-231 cells is mediated by the cell cycle arrest at S phase through the up-regulation of p27Kip1 expression. PL also suppresses invasive behavior of MDA-MB-231 cells by the inhibition of cell adhesion, cell migration and cell invasion through by suppressing the secretion of urokinase-plasminogen activator (uPA) from breast cancer cells. In addition, we have shown that PL markedly inhibits the early event in angiogenesis, capillary morphogenesis of the human aortic endothelial cells (HAEC), by down-regulating the secretion of VEGF from MDA-MB-231 cells. These effects are mediated by the inhibition of serine-threonine kinase AKT signaling, because PL suppressed phosphorylation of AKT at Thr308 and Ser473 in breast cancer cells. Taken together, our work suggests that Phellinus linteus may have a potential therapeutic effect against invasive breast cancer.

Sliva D, Jedinak A, Kawasaki J, Harvey K, Slivova V. Phellinus linteus suppresses growth, angiogenesis and invasive behavior of breast cancer cells through the inhibition of AKT signaling. Br J Cancer. in press, 2008.

Pleurotus Ostreatus

The oyster mushroom, Pleurotus ostreatus, is one of the edible mushrooms consumed in the U.S. The anticancer effects of P. ostreatus have been demonstrated in vitro and in animal studies. However, the molecular mechanism(s) responsible for the biological activities of P. ostreatus had not been elucidated. We have recently evaluated the effect of an extract from Oyster mushroom (OME) on the proliferation of human breast and colon cancer cells. We found strong inhibitory effects of OME on human colon cancer cells (HCT-116, HT-29) and breast cancer cells (MDA-MB-231, MCF-7), occurring in a dose- and time-dependent manner. Interestingly, proliferation of non-tumorigenic colon (FHC) or mammary (MCF10A) epithelial cells was not affected by OME. We demonstrated by flow cytometry that P. ostreatus induces cell cycle arrest at the G0/G1 phase in colon HT-29 and breast MCF-7 cancer cells. cDNA microarray analysis revealed that OME alters the expression of cell cycle regulatory proteins, which was confirmed by western blot analysis. Therefore, our data demonstrate that OME induces cell cycle arrest of HT-29 by up-regulating the expression of p-21, whereas cell cycle arrest of MCF-7 is induced through the up-regulation of p-53 and p-21 expression. These findings suggest that consumption of the dietary mushroom, P.em> ostreatus, could inhibit the growth of colon and breast cancer cells specifically, without any effect on normal cells.

Jedinak A, Sliva D. Pleurotus ostreatus inhibits proliferation and modulates expression of cell cycle regulatory proteins in human breast and colon cancer cells. 2008.