Biography:

Pandurangan Ramaraj is currently working in Department of Biochemistry, Kirksville College of Osteopathic Medicine, A.T.Still University of Health Sciencesrn, USA

Abstract:

Epidemiological SEER data showed a higher mortality rate in males than females in melanoma, suggesting a sex difference. Clinical findings that menstruating females were better protected in melanoma than post-menopausal women and men of any age, suggested the involvement of sex hormones in protecting menstruating females. But, these studies did not show any direct effect of sex hormone on melanoma cell growth. Our previous studies with mouse and human melanoma cell lines showed the direct effect of progesterone, a female sex hormone inhibiting the cell growth significantly. This observation raised the question whether androgens (DHEA, AD and T) were responsible for increased male mortality in melanoma, as androgens levels were higher in males than in females. But literature survey showed that androgens were essential for healthy skin. Androgens were involved in sebaceous gland growth and differentiation, wound healing, hair growth. So, we checked the effect of androgens on mouse melanoma (B16F10) cell growth in-vitro. Results showed that androgens [androstenedione (AD) and testosterone (T)] also inhibited melanoma cell growth in-vitro. In addition, supplementation of progesterone as low as 10 mM concentration to androgens showed a significant additive effect on the inhibition of cell growth in-vitro. This observation raised the question whether lack or deficiency of progesterone in males was responsible for increased mortality in males. So the study was extended to human melanoma (BLM) cells. Results showed that AD and T inhibited human melanoma cell growth also, but at 100 and 200 mM concentrations. Again addition of progesterone as low as 10 mM concentration to androgens showed an additive effect on melanoma cell growth inhibition on top of maximum inhibition by androgens alone.
Conclusion: These observations suggested that androgens might not be responsible for increased male mortality in melanoma, perhaps the deficiency of progesterone in males that increased male mortality in melanoma. This study was in line with a published study which showed a significant correlation between circulating estrogen and male breast cancer. This study was able to provide a possible biological basis of SEER data and also a possible biological basis of protection enjoyed by menstruating females in melanoma.rn

Biography:

Professor Donald Poirier received his training in chemistry (B.Sc., 1977-1980) and organic chemistry (PhD, 1980-1985) at Université Laval (Québec City, Canada). He subsequently specialized in medicinal chemistry (Post-doctoral training at CHUL - Research Center, 1986-1990) and more recently in solid phase synthesis of small molecules of therapeutic interest. He is especially interested in the development of inhibitors of steroidogenic enzymes (17b-hydroxysteroid dehydrogenases (types 1, 2, 3, 7, 10 and 12) and steroid sulfatase) and antitumor agents for the treatment of different cancers (breast, prostate, ovary, leukemia). In addition to the synthesis of small molecules by classical chemistry, he succeeded by developing solid-phase synthesis of C18-steroid (estrane), C19-steroid (androstane) and C21-steroid (pregnane) derivatives that enabled the generation of model libraries of targeted therapeutic compounds. Thus, he developed a new sulfamate linker for solid-phase synthesis that produces two classes (phenol and sulfamate) of relevant steroidal or nonsteroidal compounds according to the conditions of cleavage. He also developed a diethylsilylacetylene linker to generate libraries of acetylenic tertiary alcohols, which are well known to be biologically more stable than their corresponding secondary alcohols.

He is also interested to additional aspects of organic chemistry (synthesis, new methodologies, NMR analysis, etc.) and medicinal chemistry (structure-activity relationships, molecular modelisation, biological assays, etc.). He is professor at the Department of Molecular Medicine (Faculty of Medicine, Université Laval, Québec City, Canada) since July 1991, researcher at CHU de Québec - Research Center (Québec City) since 1991 and director of the Organic Synthesis Service (CHU de Québec) since 2008. Professor Poirier is member of professional organizations such as ACS, CIC, OCQ, ACFAS and CRCQ. He published 202 papers and 8 patents. He was also author or co-authors of 414 presentations (invited speaker, oral and poster presentations).

Abstract:

The development of cytotoxic agents that selectively promote the apoptosis of cancer cell while limiting the death of normal cells would represent a significant breakthrough in cancer therapy. The aminosteroid derivative RM-133 was recently developed in our research group as anticancer agents. RM-133, or {4-[(2β,3α,5α,17α)-3,17-dihydroxypregn-20-yn-2-yl]piperazin-1-yl}[(2S)-1-(quinolin-2-ylcarbonyl)pyrrolidin-2-yl]methanone, was synthesized from androsterone using a sequence of six steps in an overall yield of 14%. It is a promising selective pro-apoptotic agent showing antiproliferative activity (IC50 ranging from 0.1 to 4.5 µM) on various human cancer cell lines (HL-60, PANC-1, LNCaP, LAPC-4, MCF-7, T-47D and OVCAR-3). For in vivo assessment on animal models (xenografts), nude mice were inoculated in both flanks with human cancer cells (HL-60, MCF-7, PANC-1 or OVCAR-3) and tumors obtained after two-three weeks were treated or not with RM-133 using a mixture of ethanol (EtOH) and propylene glycol (PG) or dimethyl sulfoxide (DMSO) and 0.4% aqueous methylcellulose (MC) as vehicle for subcutaneous (sc) injection. The tumor size was measured twice weekly and the result expressed as percentage of the initial tumor. In a first series of experiments, RM-133 reduced the tumor growth of all four tested xenografts: HL-60 cells (leukemia) by 58% (60 mg/kg/day, sc, EtOH:PG/8:92), MCF-7 cells (breast cancer) by 60-84% (60 mg/kg/day, sc, EtOH:PG/8:92), PANC-1 cells (pancreas cancer) by 63% (240 mg/kg/2 days, sc, EtOH:MC/8:92), OVCAR-3 cells (ovary cancer) by 50% (60 mg/kg/day, sc, EtOH:MC/8:92). When tested at higher dose on the OVCAR-3 xenograft tumor model, RM-133 (2 x 240 mg/kg/2 days, sc, EtOH:MC/8:92) fully blocked (100%) the tumor growth. RM-133 was also well tolerated by mice and no weight loss was recorded. These interesting results, especially those obtained for two refractory cancers (pancreas and ovary), encourage us to pursue the optimization and mechanistic studies. In summary, steroid derivatives were synthesized and generated promising in vivo results against a series of cancer tumor models.