There are mainly three types of propolis whose major anticancer ingredients are entirely different: (1) CAPE (caffeic acid phenethyl ester)-based propolis in Europe, Far East and New Zealand, (2) artepillin C (ARC)-based Brazilian green propolis and (3) Brazilian red propolis. It was shown previously that NF (neurofibromatosis)-associated tumors require the kinase PAK1 for their growth, and CAPE-based propolis extracts such as Bio 30 suppress completely the growth of NF tumors in vivo by blocking PAK1 signaling. Also it was demonstrated that ARC suppresses angiogenesis, suggesting the possibility that ARC also blocks oncogenic PAK1 signaling. Here it is shown for the first time that both ARC and green propolis extract (GPE) indeed block the PAK1 signaling selectively, without affecting another kinase known as AKT. Furthermore, it was confirmed that ARC as well as GPE suppress almost completely the growth of human NF tumor xenografts in mice, as does Bio 30. These results suggest that both CAPE-based and ARC-based propolis extracts are natural anti-PAK1 remedies and could be among the first effective NF therapeutics available on the market. Since more than 70% of human cancers such as breast and prostate cancers require the kinase PAK1 for their growth, it is quite possible that GPE could be potentially useful for the treatment of these cancers, as is Bio 30.

(1-4) Class I enzymes (topo I, EC 5.99.1.2) act by making a transient break in one DNA strand, allowing the DNA to swivel and release torsional strain, changing the linking number by steps of one.(2,4) Class II enzymes (topo II, EC 5.99.1.3) make transient breaks in both strands of one DNA molecule, allowing the passage of another DNA duplex through the gap, changing the linking number by steps of two.(1-3) These enzymes are crucial for cellular genetic processes such as DNA replication, transcription, recombination, and chromosome segregation at mitosis.It has long been accepted that topos are valuable targets of cancer chemotherapeutics.(2-5) Several classes of topo inhibitors have been introduced into cancer clinics as potent anticancer drugs, including camptothecin (CPT) derivatives (e.g. irinotecan and topotecan) inhibiting topo I (4) and anthracyclines (e.g. doxorubicin and mitoxantorone), epipodophyllotoxins (e.g. etoposide , aminoacridines (e.g. m-AMSA) and ellipticines targeting topo II.(4,5) These agents are active in both hematological and solid malignancies. The activity of these agents is thought to result from stabilization of the DNA /topo cleavable complex (CC), an intermediate in the catalytic cycle of the enzymes, (2,5,6) resulting ultimately in apoptosis. A number of new topo inhibitors have recently been reported that do not stabilize CC. Thus, two general mechanistic classes of topo inhibitors, especially for topo II, have recently been described: (7) (1) classical topo 'poisons' that stabilize CC and stimulate single-or double-strand cleavage of DNA, such as CPT and its derivatives, indolocarbazoles for topo I, and for topos I and II; and (2) catalytic inhibitors that prevent the catalytic cycle of the enzymes at steps other than cleavage intermediates, such as dioxopiperazines, (7,9,10) aclarubicin, (11) intoplicin, (12) and F11782.(13) Some of these compounds are dual inhibitors of topos I and II. The catalytic inhibitors of topo II, merbarone (14,15) and dioxopiperazines, (9,10) have been extensively studied and have been shown to inhibit the reopening of the closed clamp formed by the enzyme around DNA by inhibiting the ATPase activity of the enzyme, thus sequestering the enzyme within the cell. (7,16,17)

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Tyrosinase is the key enzyme involved in melanogenesis. The aim of this study was to investigate the in vitro inhibitory effects of gnetin C, a resveratrol dimer isolated from melinjo (Gnetum gnemon) seeds, on tyrosinase activity and melanin biosynthesis in murine B16 cells. The inhibitory activities of gnetin C and resveratrol were shown to be almost equal against tyrosinase and melanin biosynthesis in the cells. The IC 50 values of gnetin C activity against tyrosinase and melanin biosynthesis were 7.0 and 7.6 µM, respectively, whereas resveratrol demonstrated IC 50 values of 7.2 and 7.3 µM, respectively. These results indicated that gnetin C inhibited melanogenesis, in a manner similar to that of resveratrol, by inhibiting tyrosinase and may therefore function as a new skin-whitening agent. However, the direct effects of gnetin C and resveratrol on murine tyrosinase activities were not equal. The IC 50 value of resveratrol was 10.1 µM, while gnetin C only exhibited a 25.2% enzyme inhibition at 16 µM. The IC 25 values for gnetin C and resveratrol were 15.5 and 4.0 µM, respectively. Therefore, it is suggested that the effects of gnetin C may be due to mechanisms other than the direct inhibition of tyrosinase activity.

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