Brian A. Vesely

Four peptides decrease the number of human pancreatic adenocarcinoma cells

Background  Long‐acting natriuretic peptide, vessel dilator, kaliuretic peptide and atrial natriuretic peptide are four peptide hormones synthesized by the same gene. Their main known biologic properties are sodium and water excretion and blood pressure lowering in both animals and humans.

Almiramides A−C: Discovery and Development of a New Class of Leishmaniasis Lead Compounds

Leishmaniasis is a debilitating disease caused by protozoan parasites of the genus Leishmania, which affects an estimated 12 million people worldwide. The discovery of new lead compounds for leishmaniasis is therefore a pressing concern for global health programs. The organic extract of a Panamanian collection of the marine cyanobacterium Lyngbya majuscula showed strong in vitro activity in two complementary screens against the tropical parasite Leishmania donovani, the causative agent of visceral leishmaniasis. Chromatographic separation of this complex mixture led to the isolation of the highly N-methylated linear lipopeptides, almiramides A-C (1-3). Comparison with the biological activities of a number of related metabolites and semisynthetic derivatives revealed key features required for activity and afforded one new compound (11) with superior in vitro activity. Subsequent synthesis of a library of simplified analogues led to the discovery of several compounds with improved therapeutic indices to the natural products.

Four peptide hormones decrease the number of human breast adenocarcinoma cells

Background  A family of six hormones, i.e. atrial natriuretic peptide, brain natriuretic peptide, C‐natriuretic peptide, long‐acting natriuretic peptide, vessel dilator, and kaliuretic peptides main known biologic properties are sodium and water excreting and blood pressure lowering.

Urodilatin and four cardiac hormones decrease human renal carcinoma cell numbers

Background Mortality from renal‐cell cancer remains a significant problem with an estimated 12 600 deaths in the United States in 2005 even with current treatment(s) of surgery, chemotherapy, radiation and immunotherapy. Four cardiac natriuretic peptides, that is, atrial natriuretic peptide, vessel dilator, long‐acting natriuretic peptide and kaliuretic peptide have significant anti‐cancer effects in breast, pancreatic, prostate and colon adenocarcinomas.

Four peptide hormones’ specific decrease (up to 97%) of human prostate carcinoma cells

Background  Mortality from prostate cancer remains a significant problem with current treatment(s), with an expected 30 350 deaths from prostate cancer in 2005. Long‐acting natriuretic peptide, vessel dilator, kaliuretic peptide and atrial natriuretic peptide have significant anticancer effects in breast and pancreatic adenocarcinomas. Whether these effects are specific and whether they have anticancer effects in prostate adenocarcinoma cells has not been determined.

Five cardiac hormones decrease the number of human small-cell lung cancer cells.

Background  Four peptide hormones of a family of six hormones, i.e. atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C‐natriuretic peptide (CNP), long acting natriuretic peptide (LANP), vessel dilator and kaliuretic peptide, significantly decrease the number of adenocarcinoma cells in culture. The present investigation was designed to determine whether these peptide hormones’ effects are specific to adenocarcinomas or whether they might decrease the number of cancer cells of a different type of cancer, i.e. small‐cell lung cancer.

Four peptides decrease human colon adenocarcinoma cell number and DNA synthesis via cyclic GMP

AbstractBackground: Mortality from colon cancer is significant with an expected 30,350 colon cancer deaths in 2005 with current treatment(s). Long-acting natriuretic peptide, vessel dilator, kaliuretic peptide, and atrial natriuretic peptide have significant anticancer effects in breast and pancreatic adenocarcinomas. Aim of Study: Whether these peptide hormones have anticancer effects in colon adenocarcinoma cells and whether these effects are specifically mediated by cyclic GMP has not been determined. Methods: These peptide hormones were evaluated for anticancer effects in human colon adenocarcinoma cells and to determine whether their anticancer effects are specifically mediated by cyclic GMP. Results: There was a 89–97% decrease (p<0.001 for each) in colon adenocarcinoma cells within 24 h with 1 mM of these peptide hormones. There was a significant (p<0.05) decrease in human colon cancer cell number with each 10-fold increase in concentration from 1 to 1000 µM (i.e., 1 mM) of these four peptide hormones without any proliferation in the 3 d following this decrease. These same hormones decreased DNA synthesis 65–83% (p<0.001). Cyclic GMP antibody inhibited 75–80% of these peptides’ ability to decrease colon adenocarcinoma cell number and inhibited 92–96% of their DNA synthesis effects and 97% of cyclic GMP’s effects. Western blots revealed that for the first time natriuretic peptide receptors (NPR) A and C were present in colon adenocarcinoma cells. Conclusions: Four peptide hormones eliminate up to 97% of colon cancer cells within 24 h with their DNA effects specifically mediated by cyclic GMP.

Antileishmanial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-diamines

A series of N2,N4-disubstituted quinazoline-2,4-diamines has been synthesized and tested against Leishmania donovani and L. amazonensis intracellular amastigotes. A structure–activity and structure–property relationship study was conducted in part using the Topliss operational scheme to identify new lead compounds. This study led to the identification of quinazolines with EC50 values in the single digit micromolar or high nanomolar range in addition to favorable physicochemical properties. Quinazoline 23 also displayed efficacy in a murine model of visceral leishmaniasis, reducing liver parasitemia by 37% when given by the intraperitoneal route at 15 mg kg–1 day–1 for 5 consecutive days. Their antileishmanial efficacy, ease of synthesis, and favorable physicochemical properties make the N2,N4-disubstituted quinazoline-2,4-diamine compound series a suitable platform for future development of antileishmanial agents.

Four cardiac hormones cause cell death of melanoma cells and inhibit their DNA synthesis.

Background:There will be an estimated 59,940 new cases of melanoma and 8,110 deaths from melanoma in the United States in 2007. There has been no improvement in survival with melanomas in the last 22 years, with current treatment indicating that new treatment(s) of melanoma are drastically needed. Four cardiac hormones ie, atrial natriuretic peptide, vessel dilator, long-acting natriuretic peptide, and kaliuretic peptide, have significant anticancer effects in adenocarcinomas. Methods:Dose-response curves evaluated the effects of these cardiovascular hormones on cell death and DNA synthesis in several melanoma cell lines in culture for 96 hours. Receptors to mediate these peptide hormones effects were examined in the melanoma cells with Western blots. Their intracellular mediator-analog 8-bromo-cyclic GMP was used to determine if it could mimic their effects on decreasing melanoma cell number and DNA synthesis. Results:The four cardiac hormones caused cell death in up to 71% (P < 0.001) of the melanoma cells within 24 hours. Cardiac hormone receptors (NPR-A, -B, -C) were present on the melanoma cells, and each of the peptide hormones decreased DNA synthesis within the melanoma cells up to 73% (P < 0.001) at their 1-&mgr;M concentrations. 8-Bromo-cyclic GMP mimicked their effects, decreasing the number of melanoma cells up to 67% and their DNA synthesis by 58% (both at P < 0.01). Conclusions:These results indicate that 4 cardiac hormones have potent beneficial effects by increasing cell death in up to 71% of melanoma cells within 24 hours mediated in part by a 73% decrease in their DNA synthesis.

Primary malignant tumors of the heart: four cardiovascular hormones decrease the number and DNA synthesis of human angiosarcoma cells.

Background: A family of six cardiovascular hormones – atrial natriuretic peptide, brain natriuretic peptide, C-natriuretic peptide, long acting natriuretic peptide, vessel dilator and kaliuretic peptide – was investigated for the ability to decrease the number of human angiosarcoma cells. Methods and Results: Within 24 h, vessel dilator, long acting natriuretic peptide, kaliuretic peptide, atrial natriuretic peptide and their intracellular mediator cyclic GMP decreased the number of angiosarcoma cells by 61, 30, 29, 36 and 32%, respectively, and DNA synthesis by 68–85%. Brain natriuretic peptide and C-natriuretic peptide had no effect(s). The natriuretic peptide receptor C was present. Conclusions: Four cardiovascular hormones decrease the number of angiosarcoma cells within 24 h via inhibition of DNA synthesis mediated in part by cyclic GMP.