- Methodist Research Institute
- BASIC SCIENCE RESEARCH
- CLINICAL RESEARCH GROUP
- MEDICAL RESEARCH LABORATORY
- BIOSTATISTICS & DATA SERVICES
- BIOMEDICAL COMMUNICATION
- Medical Library
Daniel Sliva, PhD
Medodist Research Institute
Indiana University Health
1800 N. Capitol Avenue
Indianapolis, IN 46202
The Cancer Research Laboratory studies how natural compounds and dietary products affect the growth, invasiveness, and metastatic behavior of cancer cells at the molecular level. The association of immune cells and cancer has been known for over a century. Emerging evidence indicates that tumor microenvironment plays a crucial role in tumor formation and progression, and macrophages are key players in inflammatory processes as well as key effector cells in the tumor microenvironment. Because the inhibition of invasive behavior of cancer cells and the modulation of immune response of macrophages can result in the suppression of cancer progression and metastasis, dietary interventions might help in the prevention and nutritional treatment of cancer.
We have recently demonstrated that extracts from medicinal mushrooms (Ganoderma lucidum, Phellinus linteus) or edible (Pleurotus ostreatus) mushrooms suppressed cancer cell proliferation, angiogenesis, and invasiveness by inhibiting the expression of specific target genes and suppressed inflammatory response in vitro and in vivo. We have also demonstrated that mushroom extracts or mushroom based dietary supplements suppressed growth and metastasis of colon, prostate and breast cancers in laboratory animals. Moreover, some of these mushrooms extract also demonstrated anti-diabetic and anti-obese properties.
The Cancer Research Laboratory collaboration with IUPUI resulted in the chemical synthesis de novo of the biologically active triterpene from the mushroom, G. lucidum, ganodermanontriol (GDNT), and we have found that GDNT specifically inhibits CDC20, cell cycle regulatory protein, which is over-expressed in tumors in breast cancer patients. In addition to the laboratory research projects, the members of the Cancer Research Laboratory actively participate in supervising college summer students in the MRI and IU Summer Student Research Programs.
Cancer Progression, Metastasis, and Inflammation
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 2009. 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 over-expression 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. The interaction of macrophages with colon cancer cells induced growth and invasive behavior in colon cancer cells, and stimulated angiogenesis of endothelial cells. Therefore, the disruption of signaling that mediates the interaction between macrophages and cancer cells can provide new targets for the suppression of invasive cancers.
Anti-cancer, anti-metastatic, and anti-inflammatory natural products
We are currently evaluating a variety of natural products for their potency to change the invasive (mesenchymal) phenotype to the non-invasive (epithelial) phenotype of cancer cells, and the mechanisms of their activity. We are aiming to identify novel cancer targets, which are modulated by natural compounds and can be therefore used for the prevention and treatment of cancer. We are also working on the elucidation of mechanisms how natural compounds and chemically synthesized GDNT inhibit breast-to-lung cancer metastasis. Finally, we are assessing the mechanisms of the inhibition of inflammation, leading to the cancer, through the suppression of TLR4 signaling by natural compounds.
- Jiang J, Eliaz I, Sliva D. Synergistic and additive effects of modified citrus pectin with two polybotanical compounds, in the suppression of invasive behavior of human breast and prostate cancer cells. Integr Cancer Ther. 2013;12(2):145-52. Link
- Jiang J, Thyagarajan-Sahu A, Loganathan J, Eliaz I, Terry C, Sandusky GE, Sliva D. BreastDefend prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer. Oncol Rep. Oct 2012;28(4):1139-1145. Link
- Jiang J, Thyagarajan-Sahu A, Krchňák V, Jedinak A, Sandusky GE, Sliva D. NAHA, a Novel Hydroxamic Acid-Derivative, Inhibits Growth and Angiogenesis of Breast Cancer In Vitro and In Vivo. PLoS ONE. 2012;7(3): e34283. doi:10.1371/journal.pone.0034283. Link
- Jiang J, Slivova V, Jedinak A, Sliva D. Gossypol inhibits growth, invasiveness, and angiogenesis in human prostate cancer cells by modulating NF-kappaB/AP-1 dependent- and independent-signaling. Clin Exp Metastasis. Feb 2012;29(2):165-178. Link
- Jiang J, Loganathan J, Eliaz I, Terry C, Sandusky GE, Sliva D. ProstaCaid inhibits tumor growth in a xenograft model of human prostate cancer. Int J Oncol. May 2012;40(5):1339-1344. Link
- Thyagarajan-Sahu A, Lane B, Sliva D. ReishiMax, mushroom based dietary supplement, inhibits adipocyte differentiation, stimulates glucose uptake and activates AMPK. BMC Complement Altern Med. 2011;11:74. Link
- Kennedy EM, P'Pool SJ, Jiang J, Sliva D, Minto RE. Semisynthesis and biological evaluation of ganodermanontriol and its stereoisomeric triols. J Nat Prod. Nov 28 2011;74(11):2332-2337. Link
- Jiang J, Wojnowski R, Jedinak A, Sliva D. Suppression of proliferation and invasive behavior of human metastatic breast cancer cells by dietary supplement BreastDefend. Integr Cancer Ther. Jun 2011;10(2):192-200. Link
- Jiang J, Jedinak A, Sliva D. Ganodermanontriol (GDNT) exerts its effect on growth and invasiveness of breast cancer cells through the down-regulation of CDC20 and uPA. Biochem Biophys Res Commun. Nov 18 2011;415(2):325-329. Link
- Jiang J, Eliaz I, Sliva D. Suppression of growth and invasive behavior of human prostate cancer cells by ProstaCaid: mechanism of activity. Int J Oncol. Jun 2011;38(6):1675-1682. Link
- Jedinak A, Thyagarajan-Sahu A, Jiang J, Sliva D. Ganodermanontriol, a lanostanoid triterpene from Ganoderma lucidum, suppresses growth of colon cancer cells through ss-catenin signaling. Int J Oncol. Mar 2011;38(3):761-767. Link
- Jedinak A, Dudhgaonkar S, Wu QL, Simon J, Sliva D. Anti-inflammatory activity of edible oyster mushroom is mediated through the inhibition of NF-kappaB and AP-1 signaling. Nutr J. 2011;10:52. Link
- Jedinak A, Dudhgaonkar S, Kelley MR, Sliva D. Apurinic/Apyrimidinic endonuclease 1 regulates inflammatory response in macrophages. Anticancer Res. Feb 2011;31(2):379-385. Link
- Thyagarajan A, Jedinak A, Nguyen H, Terry C, Baldridge LA, Jiang J, Sliva D. Triterpenes from Ganoderma Lucidum induce autophagy in colon cancer through the inhibition of p38 mitogen-activated kinase (p38 MAPK). Nutr Cancer. 2010;62(5):630-640. Link
- Sliva D. medicinal mushroom Phelllinus linteus as an alternative cancer therapy (Review). Exp Ther Medicine 2010;1:407-411. Link
- Jiang J, Sliva D. Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells. Int J Oncol. Dec 2010;37(6):1529-1536. Link
- Jedinak A, Dudhgaonkar S, Sliva D. Activated macrophages induce metastatic behavior of colon cancer cells. Immunobiology. Mar 2010;215(3):242-249. Link
- Jedinak A, Dudhgaonkar S, Jiang J, Sandusky G, Sliva D. Pleurotus ostreatus inhibits colitis-related colon carcinogenesis in mice. Int J Mol Med. Nov 2010;26(5):643-650. Link
- Harvey KA, Welch Z, Sliva D, Siddiqui RA. Role of Rho kinase in sphingosine 1-phosphate-mediated endothelial and smooth muscle cell migration and differentiation. Mol Cell Biochem. Sep 2010;342(1-2):7-19. Link
- Dudhgaonkar S, Thyagarajan A, Sliva D. Suppression of the inflammatory response by triterpenes isolated from the mushroom Ganoderma lucidum. Int Immunopharmacol. Oct 2009;9(11):1272-1280. Link
- Adamec J, Jannasch A, Dudhgaonkar S, Jedinak A, Sedlak M, Sliva D. Development of a new method for improved identification and relative quantification of unknown metabolites in complex samples: determination of a triterpenoid metabolic fingerprint for the in situ characterization of Ganoderma bioactive compounds. J Sep Sci. Dec 2009;32(23-24):4052-4058. Link
Dr. Sliva earned an MSc in food and biochemical technology from the University of Chemical Technology in Praque, Czechoslovakia. He continued his study at Charles University in Prague, receiving an MSc in biochemistry and a PhD in molecular biology and genetics. He received post-doctoral training at the Karolinska Institute in Sweden; and the Walther Oncology Center at the Indiana University School of Medicine in Indianapolis.
Dr. Sliva is an associate member of the Cancer Prevention and Control Program at the Indiana University Simon Cancer Center. His research interest includes the evaluation and characterization of biological compounds and dietary products that can be used as natural agents for the prevention or treatment of cancer. He has recently demonstrated that some Asian medicinal mushrooms (Ganoderma lucidum, Phellinus linteus) or edible American oyster mushroom (Pleurotus ostreatus) suppressed growth and invasive behavior by the modulation of specific signaling pathways in breast and colon cancer cells. His laboratory has developed an animal model of the food-borne carcinogen- and inflammation- induced colon carcinogenesis and has demonstrated that an oral application of G. lucidum and oyster mushroom suppresses colon inflammation and colon carcinogenesis in mice.
Dr. Sliva’s Curriculum Vitae