Inhibition of tumor cells proliferation and migration by the flavonoid furin inhibitor isolated from Oroxylum indicum.

BACKGROUND: The medicinally active plant Oroxylum indicum (OI) has drawn considerable research interest because of its many observed biological activities. Of particular interest is its antitumorigenic activity. The plant is a rich source of flavonoids and their glycosides. Recently flavonoids have been described as inhibitors of kexin-type proteases of superfamily Proprotein Convertase Subtilisin/ Kexins (PCSKs) which have been implicated in tumor growth and malignancy. These enzymes particularly furin (PCSK3) cleaves inactive precursor growth factors into their mature forms that promote tumor growth. As a result, finding furin-inhibitors became of high interest in cancer research. In this regard, the plant OI with known anticancer activities may provide an important source. OBJECTIVE: The objective of this study is to examine and compare anti-tumorigenic activity of furin inhibitory flavonoid compounds from OI. RESULTS: Studies were conducted to evaluate the effect on CT-26 cell proliferation and migration of 4 flavonoids baicalein, chrysin, oroxylin-A and its glycoside isolated from OI. Data revealed that baicalein exhibited most potent inhibitory effect on proliferation and migration on the analyzed tumor cell line. Baicalein at 10 µM completely blocked the proliferation even after 5 days. The results are consistent with the observed in vitro anti-furin activity of baicalein as measured against a fluorogenic peptide and pro-hVEGF-C as substrates. Mature VEGF-C is a strong indicator and biomarker of tumor progression and therefore the antifurin activity may explain the observed anticancer properties of baicalein. Since baicalein is the major constituent of OI, our data provided scientific rationale for the observed anticancer activity of OI and also offered a new lead molecule for future exploration as potential antitumor agents.

Proprotein convertase inhibitory activities of flavonoids isolated from Oroxylum indicum.

BACKGROUND: Proprotein Convertases (PCs) or Proprotein Convertase Subtilisin/Kexins (PCSKs) belong to a family of calcium-dependent endoproteases that are structurally related to bacterial subtilisin and yeast kexin. These enzymes play major roles in the processing of inactive precursor proteins producing their bioactive mature forms that are implicated in a wide variety of diseases including cancer, viral and bacterial infections. As a result, PCs are major targets for intervention of these diseases. OBJECTIVE: Our objective in this study is to find non-peptide inhibitors of PC-enzymes from a potential natural source. RESULTS: Herein we describe several natural flavonoid compounds as inhibitors of PC-enzymes including furin, a key member. These compounds were isolated from the medicinal plant Oroxylum indicum, fully characterized and tested in vitro for their PC-inhibitory property against the fluorogenic peptide substrate, Boc-RVRR-MCA (Boc = tert-butyloxy carbonyl, MCA = 4-methyl coumarin7-amide). The measured Ki and IC50 were found to be in low microM ranges. A comparative analysis of inhibition against furin, PC4, PC5 and PC7 suggested a partial selectivity towards PC4. These flavonoids also blocked efficiently the PC4-mediated processing of a fluorogenic peptide derived from the processing site of its substrate, pro-Insulin Growth Factor-1 (proIGF-1). This anti-protease activity may provide a rationale for the observed anticancer and anti-HIV properties of some of these flavonoid compounds. This is the first demonstration of anti-PC activity of flavonoid compounds.