Inhibition of Proliferation

Future therapies aimed at preventing the proliferative response of ASM, observed in persistent asthma, will target those intracellular pathways which are believed to inhibit the proliferative response. Those pathways involving cGMP and cAMP, which produce relaxation of ASM, have been investigated as possible taigets for the inhibition of proliferation. 

Although activation of cGMP production inhibits vascular smooth muscle proliferation (Itoh et /., 1990 Winter, 1993), no comparable effect of cGMP has been demonstrated in ASM. 

Adelstein, R.S. (1983). Regulation of contractile proteins by phosphorylation. J. Clin. Invest. 72, 1863-1866. 

Adelstein, R.S. and Eisenberg, E. (1980). Regulation and kinetics of the actin-myosin-ATP interaction. Annu. Rev. Biochem. 49, 956-969. 

Adelstein, R.S., DeLanerolle, P., Sellers, J.R, Pato, M.D. and Conti, M.A. (1982). Regulation of contractile proteins in smooth muscle and platelets by calmodulin and cyclic AMP. In Calmodulin and Intracellular Calcium Receptors (eds S. Kakiuchi, H. Hidaka and A.R. Means), pp. 313-331. Plenum, New York. 

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Lymphocytes, inflammatory cells, intestinal mucosal cells, cartilage cells and bone precursor cells Inhibition of proliferation... 

Kelly, ME, Clay, MA, Mistry, MJ, Hsieh-Li, HM, and Harmony, JA, 1994. Apolipoprotein E inhibition of proliferation of mitogen-activated T lymphocytes Production of interleukin 2 with reduced biological activity. Cell Immunol 159, 124—139. 

The thalidomide analogs CPS49 (30) and CPS11 (31) have been reported to inhibit PI3/AKT signaling in multiple myeloma cells via an anti-angiogenic effect. These compounds are devoid of the teratogenic properties seen with thalidomide and are currently in preclinical development [66]. Compound 30, and to a lesser extent 31, induced a dose-dependent inhibition of proliferation in several multiple myeloma cell lines and reduced phospho-AKT levels [66]. These compounds also inhibited DNA synthesis in cell lines resistant to conventionally used anti-multiple myeloma drugs (e.g. dexamethasone, anthracyclines and melphalan) in a dose-dependent manner. 

HI. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclophosphamide (p. 298). The antiproliferative effect is not specific for lymphocytes and involves both T- and B-cells. 

The inhibition of proliferation of several cancer cells was investigated with the compounds shown in Fig. 8. One of these lignans, compound 143, was active, having an IC50 of ca. 35 fxmol/1 against HT 29 colon cancer cells [75] and others [76]. This result was in agreement with previously observed cytotoxicities of a-unfunctionalized lactone lignans [77]. 

The control of cell numbers is regulated by cell proliferation, differentiation and apoptosis. Increased proliferation and/or decreased apoptosis result in neoplasia. In addition to inhibition of proliferation or induction of differentiation, the modulation of apoptosis can be employed for treatment for cancer. Several anticancer agents in use are potent inducers of apoptosis (Dive and Hickman, 1991 Fisher, 1994). Tumor promotion may result in decreased apoptosis. Because PKC activation by TPA induces carcinogenesis, it seems that PKC may be involved in apoptosis. There are many reports on the effects of PKC on apoptosis. However, the results are very controversial. Here an overview of these data is presented. 

Berkovic D, Berkovic K, Fleer EA, Eibl H, Unger C (1994) Inhibition of calcium-dependent protein kinase C by hexadecylphosphocholine and l-O-octadecyl-2-O-methyI-rac-glycero-3-phosphocholine do not correlate with inhibition of proliferation of HL60 and K562 cell lines. Eur J Cancer 30A 509-515... 

Increased inhibition of proliferation and motiHty by PI3K inhibitors, linked to stronger inhibition of P-AKT... 

So FV, Guthrie N, Chambers AF, Carroll KK. Inhibition of proliferation of estrogen receptorpositive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen. Cancer Lett. 112, 127-133, 1997. 

Experiments utilizing D,L-a-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decatboxylase, to determine its effect on mitogen- or al-loantigen-induced lymphocyte proliferation and CTL induction have certain similarities to the inhibition seen in N=0-induced inhibition of lymphocyte function. Stimulation of both mouse and human T cells in the presence of DFMO results in partial inhibition of proliferation which can be reversed by addition of the polyamines putrescine, spermidine, and spermine (Bowlin et al., 1987 McCarthy et al., 1990). lL-2 levels in these lymphocyte cultute supernatants as well... 

Dehydrokuanoniamine B (127) and shermilamine C (128) were isolated from a Cystodytes sp. from Fiji. Their structures were determined by analysis of spectroscopic data. These compounds displayed dose-dependent inhibition of proliferation in human colon tumour cells in vitro [142]. Shermilamines D (129) and E (130) were... 

On the other hand, there is strong evidence that the effects of flavonoids on cultured cells are not merely toxic but via induction of apoptosis or inhibition of proliferation. Thus signs of apoptosis, such as induction of caspase-3, fragmentation of DNA and chromatin condensation, are frequently detected upon cell exposure to flavonoids [213, 217-221]. In addition, the effects of flavonoids are generally reversible upon removal or addition of serum [222-224]. 

Shermilamines B (37) and C (38) (and also diplamine 46) showed dose-dependent inhibition of proliferation in HCT cells in vitro and inhibited the topoisomerase (TOPO) II-mediated decatenation of kinetoplast DNA (kDNA) in a dose-dependent manner [41]. These results suggest a possible cytotoxicity mechanism for these compounds. Furthermore, shermilamine B also displayed cytotoxicity against KB cells [43] and was reported as a potent regulator of cellular growth and differentiation, affecting cAMP-mediated processes [44]. 

Curcumin was found to inhibit cellular proliferation and enhance apoptosis in a variety of lymphoma cell lines in vitro [Skommer et al., 2006 Thompson et al., 2004 Wu et al., 2002]. The proposed mechanism of curcumin s action in the majority of these studies involves the suppression of the expression of NF-KB-regulated gene products. One study suggested a novel function for curcumin as a suppressor of JAK-1 and STAT3 activation in primary effusion lymphoma cells, a function that would lead to the inhibition of proliferation and the induction of caspase-dependent apoptosis [Uddin et al., 2005],... 

Hsu YC, Weng HC, Lin S, Chien YW. 2007. Curcuminoids-cellular uptake by human primary colon cancer cells as quantitated by a sensitive HPLC assay and its relation with the inhibition of proliferation and apoptosis. J Agric Food Chem 20 8213-8222. 

Prakash, P., Russell, R.M., and Krinsky, N.I. 2001. In vitro inhibition of proliferation of estrogen-dependent and estrogen-independent human breast cancer cells treated with carotenoids or retinoids. J. Nutr. 131, 1574—1680. 

Harrington, E. O., Loffler, J., Nelson, P. R., Kent, K. C., Simons, M., and Ware, J. A. 1997. Enhancement of migration by protein kinase C5 and inhibition of proliferation and cell cycle progression by protein kinase C8 in capillary endothelial cells.. /. Biol. Chem. 272 7390-7397. 

Novartis Malaria Data from Gamo et al. (14), P. falciparum strains 3d7 (drug-susceptible), and W2 (chloroquine-, quinine-, pyrimethamine-, cycloguanil-, and sulfadoxine-resistant), obtained from MR4, were tested in an erythrocyte-based infection assay for susceptibility to inhibition of proliferation by selected compounds. 5,695... 

A HMG CoA reductase inhibitor, used for treatment of hypercholesterolemia, enhanced butyrate-induced inhibition of proliferation. 

Arita J, Hashi A, HoshiK, Mazawa S, Suzuki S (1998) D2 dopamine-receptor-mediated inhibition of proliferation of rat lactotropes in culture is accompanied by changes in cell shape. Neuroendocrinology 65 163-171. 

C2. Campbell, M. J., Elstner, E., Holden, S., Uskokovic, M., and Koeffler, H. P., Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafloride vitamin D3 analogue involves the induction of p21 wafl, p27kip and E-cadherin. J. Mol. Endocrinol. 19, 15-27 (1997). 

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