1 Flavonoids display a wide range of pharmacological properties including anti-in¯ammatory. Anti-mutagenic, anti-carcinogenic and anti-cancer eects. Here, we evaluated the eects of eight avonoids on the tumour cell proliferation, cellular protein phosphorylation, and matrix metalloproteinase (MMPs) secretion. 2 Of the¯avonoids examined, luteolin (Lu) and quercetin (Qu) were the two most potent agents, and signi®cantly inhibited A431 cell proliferation with IC 50 values of 19 and 21 mM, respectively. 3 The epidermal growth factor (EGF) (10 nM) promoted growth of A431 cells (+25+4.6%) and mediated epidermal growth factor receptor (EGFR) tyrosine kinase activity and autophosphorylation of EGFR were inhibited by Lu and Qu. At concentration of 20 mM, both Lu and Qu markedly decreased the levels of phosphorylation of A431 cellular proteins, including EGFR. 4 A431 cells treated with Lu or Qu exhibited protuberant cytoplasmic blebs and progressive shrinkage morphology. Lu and Qu also time-dependently induced the appearance of a ladder pattern of DNA fragmentation, and this eect was abolished by EGF treatment. 5 The addition of EGF only marginally diminished the inhibitory eect of luteolin and quercetin on the growth rate of A431 cells, treatment of cellular proteins with EGF and luteolin or quercetin greatly reduced protein phosphorylation, indicating Lu and Qu may act eectively to inhibit a wide range of protein kinases, including EGFR tyrosine kinase. 6 EGF increased the levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), while Lu and Qu appeared to suppress the secretion of these two MMPs in A431 cells. 7 Examination of the relationship between the chemical structure and inhibitory eects of eight avonoids reveal that the double bond between C2 and C3 in ring C and the OH groups on C3' and C4' in ring B are critical for the biological activities. 8 This study demonstrates that the inhibitory eects of Lu and Qu, and the stimulatory eects of EGF, on tumour cell proliferation, cellular protein phosphorylation, and MMP secretion may be mediated at least partly through EGFR. This study supports the idea that Lu and Qu may have potential as anti-cancer and anti-metastasis agents.

Pancreatic cancers overexpress tyrosine kinase and luteini'ng hormone-releasing hormone (LH-RH) receptor (LH-RHR)-mediated tyrosine phosphatase. LH-RHR is a 60-kDa protein. ligand showed that the LH-RH binding in 69% ofthe points was increased by EGF and 85% was decreased by RC-160 compared with controls (a ='61; both significant, P < 0.001). The specific binding was altered, increasing 50-150% after preincubation with EGF and decreasing 60-70% after RC-160. No change was seen in the binding affinity constant after pretreatment with EGF or RC-160. This shows that phosphorylation regulates binding of LB-RH and may explain the up-regulation by EGF and down-regulation by RC-160 and by LH-RH ofthe LH-RH response.Two lines of evidence suggest that the class of tyrosine phosphatases may be as important in cancer as the class of tyrosine kinases (1-3). These findings are based on the existence of a broad family of tyrosine phosphatase genes with receptor-like structures (4-8) and the demonstration that two hormone receptors stimulate tyrosine phosphatase activity (9)(10)(11)36). This has led to a rather unsuccessful attempt to implicate these genes as antioncogenes (tumor suppressor genes), or "emerogenes" (3, 12, 13). Investigators assumed that just as the expression of oncogenes in tissue heralds the development of cancer (14-17), the loss of expression of emerogenes should be associated with cancer development (12,13,18