Antiangiogenic Effects of Synthetic Analogs of Curcumin in vivo

The active compound curcumin is isolated from the spice turmeric. Curcumin, curcuminoids and their synthetic analogs have been shown to inhibit the progression of cancer in animal models. In colon and skin carcinogenesis the genetic changes engross different genes, but curcumin is effective in preventing carcinogenesis in both organs. A needful elucidation for this result is that analogues of curcumin can inhibit angiogenesis. The synthetic analog of Curcumin, 1,5 bis (3,5 dimethoxy phenyl) 1,4 pentadiene –3 one (BDMP) was tested for its capacity to inhibit the proliferation of primary endothelial cells in the presence and absence of the basic fibroblast growth factor (bFGF) and its ability to inhibit proliferation of an immortalized endothelial cell line. BDMP and other analogs of curcumin such as bis (3,4 dimethoxyphenyl) 1,3 propanedione (BDMPP), bis (2,4 dimethoxyphenyl) 1,3 propanedione (DMPP), and bis (3,3 dinitrophenyl) 2- bromo 1,3 propanedione (BDNP) were subsequently tested for their ability to inhibit bFGF-induced corneal neovascularization in the mouse cornea. Ultimately, BDMP was evaluated for its ability to inhibit phorbol esterstimulated vascular endothelial growth factor (VEGF) mRNA production. BDMP effectively inhibited endothelial cell proliferation in a dose dependent manner. BDMP, BDMPP, DMPP and BDNP have shown significant inhibition of bFGF mediated corneal neovascularization in the mouse. BDMP had no effect on phorbol ester stimulated VEGF production. Results of these investigations show that BDMP has direct antiangiogenic activity in vitro and in vivo. Carcinogenesis inhibiting activity of the BDMP in skin and colon may be mediated in part through angiogenesis inhibition

Plumbagin, a plant naphthoquinone with antitumor and radiomodifying properties

The tumor inhibitory and radiomodifying effects of plumbagin (Pl), a naphthoquinone isolated from Plumbago rosea, on mouse Ehrlich ascites carcinoma was studied. Tumor response was assessed by increase in life span (% ILS) and animal survival at 120 days. The acute LD50 of plumbagin in normal mice was 9.4 mg/kg body weight. Single doses from 2 to 6 mg/kg Pl, given intraperitoneally (i.p.), produced inhibition of exponentially growing armors. However increases in dose above 3 mg/kg did not increase 120 clay survival significantly over that produced by 3 mg/kg. Multiple dose treatment, starling from 24 h after tumor cell inoculation, showed that a total dose of 9 mg/kg, administered in three fractions of 3 mg/kg once daily gave the maximum %ILS and tumor free survival. Combination of radiation (RT, 7.5 Gy to the abdomen) after the first Pl dose (1-3 mg/kg/fraction) synergistically increased mouse survival at 120 clays. The tumor inhibitory effect was less pronounced when treatment was started at more advanced tumor stages, but combination of low dose fractions (2.5 or 3 mg/kg/function) with RT enhanced the %ILS and animal survival. Higher dose fractions in combination with radiation were not tolerated by the mice. DNA appears to be the likely target of PI cytotoxicity; the mechanism of interaction of Pl + RT in enhancing tumor response is not clear