Dr. Melnick is Chief of the Department of Pathology and Clinical Laboratories at Miami Children's Hospital. He joined the Department of Pathology in 1992 following his Residency training at Mount Sinai Medical Center in Miami Beach. He earned his B.Sc. in Physics and Ph.D. in Chemistry at McGill University, Montréal, Québec and his Medical Degree at Queen's University, Kingston, Ontario. He is a Diplomat of the American Board of Pathology in Anatomic and Clinical Pathology and Fellow of the College of American Pathologists. Dr. Melnick's academic interests in the field of medicinal discovery stem from research conducted at McGill University that was instrumental in establishing a research laboratory dedicated to ethnobotanical research at Miami Children's Hospital in 1999. The laboratory under his direction accumulated intellectual property including; RR1 a patented (US 7,425,548 B2) immune-modulating ?-D-glucan polysaccharide isolated from Tinospora cordifolia, a highly regarded medicinal botanical commonly used for its immune stimulating properties in Ayurvedic medicine and Amooranin, a natural pentacyclic triterpenoid drug isolated from the stem bark of Amoora rohituka, a tropical medicinal tree indigenous to the Indian subcontinent. Supported by Miami Children's Hospital, Dr. Melnick transitioned this laboratory into a start-up company; Dharma Biomedical which he founded in early 2006 and currently resides in the Research Institute at Miami Children's Hospital. The company mission remains dedicated to evidence-based ethnobotanical medicinal discovery and currently more than 20 compounds are at different stages of development. Dr. Melnick's bibliography contains over 100 peer-reviewed publications and abstracts. He is a member of medical and scientific societies including Sigma Xi, Scientific Research Society, the College of American Pathologists and the US and Canadian Academy of Pathology. He serves on a number of extra-institutional committees including the Integrative Therapeutics and Nutrition committees of the Children's Oncology Group, that largest consortium for pediatric oncology research in North America, the Scientific Committee for the Society of Integrative Oncology and is a member of the Board of Directors of the US-India Chamber of Commerce of South Florida. Dr. Melnick also serves or has served as a consultant in medical industries including the Beckman-Coulter Corporation, Abbott Laboratories and Specialty Laboratories.

Research

The main focus of my research since 1999 involves medicinal discovery from botanical compounds or natural products that have been used in the context of traditional medicine; including Ayurveda, traditional Chinese medicine, Middle Eastern and other traditional medicine systems. Additionally, this research involves a synthesis of ethnobotanical chemistry and evolutionary chemistry (evochemistry). These methodologies represent an efficient discovery paradigm since the identification of medicinal compounds or extracts is markedly enhanced by first considering a pool of botanicals and other natural products associated with enduring traditional applications and then considering the evolutionary development and biology of bioactive metabolites in these products. This approach has demonstrated the capability to identify biologically active and effective compounds for a broad range of medicinal applications with low toxicity profiles and represents an alternative to the conventional pharmaceutical paradigms of combinatorial chemistry with high throughput screening and the random selection of botanical candidates amongst the enormous diversity that exists in nature. Through this paradigm, identified extracts are characterized chemically and subjected to in vitro and in vivo analysis and potentially clinical trials. Compounds that have been identified through this process and which may have clinical relevance include:

• Amooranin, a natural patent pending pentacyclic triterpenoid drug was isolated from the stem bark of Amoora rohituka, a tropical medicinal tree indigenous to the Indian subcontinent. This novel drug is a triterpenoid compound (25-hydroxy-2-oxoolean-12-en-28-oic acid) with an oleanolic acid skeleton and is cytotoxic to an array of human tumor cell lines. This novel molecule exerts its effects through multiple mechanisms; depolarization of the mitochondrial membrane and decreased membrane potential as the initiating event of apoptosis induction, G2/M phase arrest in tumor cells in a dose-dependent manner and reversal of anthacycline resistance in MDR cell lines through binding to P-glycoprotein. The colon carcinoma xenograft mice treated with Amooranin showed significant reduction in tumor growth rate compared to saline and doxorubicin-treated groups with 2 ?g/ml being an optimal concentration. Microarray hybridization analysis of Amooranin treated colon carcinoma cells demonstrated the anticancer effects mediate several major signaling pathways.
• RR1 is a patented (US 7,425,548 B2) ?-D-glucan polysaccharide isolated from Tinospora cordifolia, a highly regarded medicinal botanical commonly used for its immunostimulating properties in Ayurvedic medicine. This polysaccharide promotes NK cell activity, Th1 pathway differentiation and macrophage activation leading to stimulation of native immunity. Both pro- and anti-inflammatory cytokines are induced by RR1 through Toll-like receptor 6 signaling and NF-kB activation with an alternate kinetics of production compared to lipopolysaccharides. In a sepsis rat model, RR1 was able to favorably alter the ratio of anti to pro-inflammatory cytokines. Since these immunostimulatory properties would be beneficial for cancer therapy, we evaluated the anticancer effect of RR1 with and without doxorubicin in an Ehrlich ascites tumor model developed in mice. In this study RR1 showed improved survival as a single agent and as an adjuvant with doxorubicin. The unique immunomodulatory properties of RR1 suggest applications in biodefense, infectious diseases, human malignancies and general immune support.
• SA-3C is a catechol derived from the fruits of Semecarpus anacardium, a tropical tree growing wild in the Indian subcontinent that is used extensively for the treatment of human cancers in the Ayurvedic medicine. The fruits of this medicinal tree resemble cashew fruits, although the seeds are flatter and smaller in size than raw cashew seeds. The nut milk extract of S. anacardium is one of the ingredients in an Ayurvedic preparation called "Kalpaamruthaa" that is reported to have antioxidant, analgesic, and antipyretic properties. The isolated anticancer principle, 3-[8'(Z),11'(Z)-pentadecadienyl]catechol (SA-3C) is derived from the kernels of S. anacardium nuts. The IC50 values of SA-3C are quite comparable to or better than that of chemotherapeutic agents like doxorubicin with cytotoxicity directed toward a variety of cancer cell lines. SA-3C has almost identical sensitivity in both sensitive and multidrug resistant cell lines. Results also indicate that the combinations of SA-3C and conventional chemotherapeutic drugs may be more advantageous than single agents and therefore, SA-3C can be developed as an adjuvant chemotherapeutic agent.

Selected Publications

1. Ramachandran C, Resek AP, Escalon E, Aviram A, Melnick SJ. Potentiation of gemcitabine by Turmeric ForceTM in pancreatic cancer cell lines. Int J Oncol 2010; 6:1529-1535.
2. Nair PKR, Melnick SJ, Wnuk SF, Rapp M, Escalon E, Ramachandran C. Isolation and characterization of an anticancer compound from Semecarpus anacardium. J Ethnopharmacol 2009; 22:450-456.
3. Cochrane CB, Nair PKR, Melnick SJ, Resek AP, Ramachandran C. Anticancer effects of Annona glabra plant extracts in human Leukemia cell lines. Anticancer Res 2008;28:965-972.
4. Qiu J, Ai L, Ramachandran C, Yao B, Gopalakrishnan S, Fields R, Delmas A, Dyer LM, Melnick SJ, Yachnis AT, Schwartz PH, Fine HA, Brown KD, Robertson KD. Invasion suppressor cystatin E/M (CST6): high-level cell type-specific expression in normal brain and epigenetic silencing in gliomas. Lab Invest 2008; 88:910-925.
5. Ramachandran C, Nair PKR, Clement R, Melnick, SJ. 2007. Investigations on cytokine expression in human leukocyte cultures with two immune-modulatory homeopathic preparations. J Altern Complement Med 2007; 4:303-407.
6. Nair PKR, Melnick SJ, Ramachandran R, Escalon E, Ramachandran C. Mechanism of macrophage activation by (1,4)-?-D-glucan isolated from Tinospora cordifolia. International Immunopharmacology 2006;6:1815-1824.
7. Ramachandran C, Nair PKR, Alamo A, Cochrane BC, Escalon E, Melnick SJ. Anticancer effects of amooranin in human colon carcinoma cell line in vitro and in nude mice xenografts. Int J Cancer 2006;5: 2443-2454.
8. Melnick SJ. Developmental therapeutics: Review of biologically based CAM therapies for potential application in children with cancer. Part II. J Pediatr Hematol Oncol 2006; 28:271-285.
9. Melnick SJ. Developmental therapeutics: Review of biologically based complementary and alternative medicine (CAM) therapies for potential application in children with cancer Part I. J Pediatr Hematol Oncol 2006; 28:221-230.
10. Ramachandran C, Rodriguez S, Ramachandran C, Nair PKR, Fonseca H, Khatib Z, Escalon E, Melnick SJ. 2005. Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines. Anticancer Res 2005; 25:3291-3302.
11. Nair PKR, Rodriguez S, Ramachandran R, Alamo A, Melnick SJ, Escalon E, Garcia Jr PI, Wnuk SF, Ramachandran C. Immune stimulating properties of a novel polysaccharide from the medicinal plant Tinospora cordifolia. International Immunopharmacology. 2004; 4:1645-1659.
12. Ramachandran C, Khatib Z, Pefkarou A, Fort J, Fonseca HB, Melnick SJ and Escalon E. Tamoxifen modulation of etoposide cytotoxicity involves inhibition of protein kinase C activity and insulin-like growth factor II expression in brain tumor cells. J Neuro-Oncol 2003; 67:19-28.
13. Toi M, Imai A, Ramachandran C, Melnick SJ, Fife R, Carr RE, Neenan I, Kaplan B, Lansky E. Pomegranate extracts inhibit both induction of angiogenic molecules from tumor cells and endothelial growth directly. Angiogenesis 2003; 6:121-128.
14. Rabi T, Ramachandran C, Fonseca HB, Alamo A, Melnick SJ, Escalon E. Novel drug amooranin induces apoptosis through caspase activity in human breast carcinoma cell lines. Breast Cancer Res Treat 2003; 80,421-330.
15. Ramachandran C, Rabi T, Fonseca HB, Melnick SJ, Escalon EA. Novel plant terpenoid drug amooranin overcomes multidrug resistance in human leukemia and colon carcinoma cell lines. Int J Cancer 2003; 105:784-789.