Inhibition of growth and guanylate cyclase activity of an undifferentiated prostate adenocarcinoma by an extract of the balsam pear (Momordica charantia abbreviata).

Abstract

We have recently described the presence of a guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.21 inhibitor (GCI) in an aqueous extract of the balsam pear (Momordica charantia abbreviata). Because the guanylate cyclase-cyclic GMP system is thought to be involved in cell growth, DNA and RNA synthesis, and possibly malignant transformation, we examined the effect of the aqueous extract containing GCI on an undifferentiated adenocarcinoma of the rat prostate and concanavalin-A-stimulated [3Hlthymidine incorporation into cultured splenic lymphocytes, a process thought to be mediated by cyclic GMP. The results demonstrate that the extract of the balsam pear blocks both the growth of the rat prostatic adenocarcinoma in vitro and [3H thymidine incorporation into DNA. DNA histograms from flow cytometry indicated that the extract containing GCI inhibited in the G2 + M phase of the cell cycle, a presumed locus of cyclic GMP effects. In addition, guanylate cyclase activity was significantly greater in the tumor than normal prostate tissue and was decreased by the extract containing GCL Cyclic GMP levels in the tumor in culture were also decreased by addition of the extract. It remains to be determined whether or not the anti-tumor agent and GCI are the same substance.The balsam pear (Momordica charantia abbreviata) is a plant that grows wild throughout subtropical regions of the world, including Florida and the Gulf Coast of the United States; We have recently reported (1) that an aqueous extract of the ripe fruit of the balsam pear contains an inhibitor of guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2], the enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to guanosine 3',5'-monophosphate (cyclic GMP). The guanylate cyclase inhibitor (GCI) blocked both the basal activity of guanylate cyclase and the activation of guanylate cyclase by nitroso chemical carcinogens (1). The latter finding was of particular interest because current evidence suggests that the major role of cyclic GMP in cell biology is concerned with cell growth, DNA and RNA synthesis, and possibly malignant transformation (2-12). A recent investigation by Zeilig and Goldberg (12), using Novikoff rat hepatoma cells, showed that, as these synchronized cells entered mitosis, cellular cyclic GMP levels rose and cellular adenosine 3',5'-monophosphate (cyclic AMP) levels declined. As the cells entered the quiescent stages of growth, the ratios of these nucleotides reversed, with cyclic AMP levels rising and cyclic GMP levels reaching their nadir. It seemed worthwhile, therefore, to determine the effects of the extract on both tumor cells and normal cells.In the present investigation we utilized cell cultures of an undifferentiated adenocarcinoma of the rat prostate, observed MATERIALS AND METHODS Cell Source and Cultivation. The prostatic adenocarcinoma cells in tissue culture were derived from the hormone-responsive G subline of the Dunning R3327 tumor. A subcutaneous G tumor in the 22nd in vivo passag...

Pharmacological actions and potential uses of Momordica charantia: a review

“…Detailed studies showed that MC acted through inhibition of cell cycle G2 and M phases (Claflin et al, 1978) through inhibition of incorporation of thymidine, leucine and uridine into DNA (Claflin et al, 1978;Chan et al, 1992;Ng et al, 1994). In addition, inhibition of guanylate cyclase activity (Vesely et al, 1977;Claflin et al, 1978;Takemoto et al, 1980Takemoto et al, , 1982b, activation of NK cells (Jilka et al, 1983;Cunnick et al, 1990;Porro et al, 1993), induction of apoptosis Sun et al, 2001) and modulation of biotransformation and detoxification enzymes of the host were also seen with MC (Kusamran et al, 1998;Singh et al, 1998;Ganguly et al, 2000).…”

“…In addition, inhibition of guanylate cyclase activity (Vesely et al, 1977;Claflin et al, 1978;Takemoto et al, 1980Takemoto et al, , 1982b, activation of NK cells (Jilka et al, 1983;Cunnick et al, 1990;Porro et al, 1993), induction of apoptosis Sun et al, 2001) and modulation of biotransformation and detoxification enzymes of the host were also seen with MC (Kusamran et al, 1998;Singh et al, 1998;Ganguly et al, 2000). Lee et al (1998) demonstrated inhibition of tumor-promoting signals from the extracellular environment to nuclear transcription machinery as well as protein-DNA interaction with momordin treatment.…”

“…An aqueous extract of MC caused inhibition of prostatic adencarcinoma growth (Claflin et al, 1978), and exerted cytostatic as well as cytotoxic activities against human leukemic lymphocytes (Takemoto et al, 1982a). The methanol extract as well as momordin I, Id and Ie of MC also showed cell cytotoxicity against human cancer cell lines (Lee et al, 1998).…”

“…Moreover it has guanylate cyclase enzyme inhibiting property (Vesely et al, 1977;Claflin et al, 1978;Takemoto et al, 1982b) that is reported to be helpful in the treatment of psoriasis (http://www.viable-herbal.com/singles/herbs/s; http://www.raintree.com/bitmelon).…”

Guanylate Cyclase Activity in Human Leukemic and Normal Lymphocytes

“…An extract from the bitter melon ripe fruit and leaves is reported to inhibit guanylate cyclase activity specifically and to block acti vation by nitroso chemical carcinogens [4,5]. We have found that this extract also inhibits guanylate cyclase from human lymphocytes, is specifically cytotoxic to leukemic human lymphocytes, and lowers cellular cyclic GMP Guanylate cyclase, the enzyme that cata lyzes the formation of cyclic GMP from GTP, exists in both soluble and particulate fractions of most tissues [1][2][3].…”