Frondoside A from sea cucumber and nymphaeols from Okinawa propolis: Natural anti-cancer agents that selectively inhibit PAK1 &lt;i&gt;in vitro &lt;/i&gt;

Nguyen, Binh Cao Quan; Yoshimura, Kazuki; Kumazawa, Shigenori; Tawata, Shinkichi; Miyata, Hiroshi

doi:10.5582/ddt.2017.01011

Cited by 53 publications

(45 citation statements)

References 13 publications

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“…Thus, there is a possibility that R3 somehow blocks PAK1, leading to the down-regulation of COX-2. During 2014-2015, we confirmed that R3 directly inhibits PAK1 in vitro with IC 50 = 15 μM, and identified a variety of more potent herbal PAK1-inhibitors such as FRA (Frondoside A) from sea cucumber and Nymphaeols from Okinawa propolis [20,28]. Finally, in 2014, a Korean group found that R3 indeed inhibits UVinduced melanogenesis in guinea pig skin [29].…”

Section: Resveratrolmentioning

confidence: 55%

“…It contains a series of geranylated flavonoids such as Nymphaeols A-C [13]. In 2016, we found that Okinawa Propolis (OP) as well as its ingredients Nymphaeols A-C directly inhibit PAK1 in vitro, and suppress the growth of A549 lung cancer cells with IC 50 around 12 μg/ml [20]. Furthermore, we found that OP extends the healthy lifespan of C. elegans at 1 μg/ml [13], and inhibits melanogenesis of B16F10 melanoma by down-regulating their tyrosinase level with IC 50 around 30 μg/ml [13].…”

Section: Nymphaeols A-cmentioning

confidence: 99%

“…Curcumin directly inhibits PAK1 in vitro with IC 50 around 16 μM [20], and the growth of a variety of cancer cells such as A549 with IC 50 around 23 μM [20]. Curcumin also has been shown to extend the lifespan of nematode [21].…”

Section: Curcuminmentioning

confidence: 99%

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Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway

Miyata¹,

Pham-Thi²,

Ahn³

2017

J Dermatol Res Ther

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A natural sleeping pill and "elixir" (longevity-promoter) called "Melatonin" is one of the first natural anti-melanogenic compounds, and originally derived from bovine pineal glands. However, currently the majority of melatonin product in the market is chemically synthesized. Since then a wide variety of anti-melanogenic compounds such as curcumin, CAPE (Caffeic Acid Phenethyl Ester), and Artepillin C (ARC) were identified in nature as well as chemically synthesized compounds such as Gleevec. These anti-melanogenic compounds share a series of interesting biological properties such as anti-cancer, anti-inflammatory, anti-ageing (longevity-promoting), immune-boosting, anti-malaria, and anti-diabetic activities. However, the precise molecular mechanism underlying their anti-melanogenic action has remained to be clarified until recently. Finally we found the first clue to understanding of the "melanogenic" signalling pathway involving the major oncogenic/ageing kinase called PAK1 (RAC/CDC42-activated kinase 1) By siRNA-based silencing of PAK1 gene in murine melanoma cell line (B16F10): (i) The major growth hormone in serum called PDGF (Platelet-Derived Growth Factor) is essential for the inducible melanogenesis, but not for the exponential growth per se, and (ii) This cytokine activates its receptor called PDGFR, a Tyr-kinase on the cell surface, and induces another cell surface receptor Tyr-kinase called EGFR (Epidermal Growth Factor Receptor), to form a heterodimer with PDGFR, activating the down-stream melanogenic/oncogenic signalling pathway involving PAK1 and eventually MITF (Microphthalmia-Associated Transcription Factor) essential for expression of Tyrosinase and its Related Protein (TRP) genes. Melatonin and many other anti-melanogenic compounds block PAK1 directly or indirectly, and eventually down-regulate tyrosinase or TRP which is essential for melanin biosynthesis from an amino acid called tyrosine.

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Section: Resveratrolmentioning

confidence: 55%

Section: Nymphaeols A-cmentioning

confidence: 99%

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Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway

Miyata¹,

Pham-Thi²,

Ahn³

2017

J Dermatol Res Ther

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“…However, it should be worth proposing the following (far less expensive and quicker) alternative approach: a highly cell-permeable potent anti-cancer agent called frondoside A (FRA), a sulphated saponin, from a sea cucumber directly inhibits PAK1 with IC 50 around 1 μM, and AKT with IC 50 around 60 μM (19). If FRA fails to inhibit the tube formation around at 1 μM, but works around at 60 μM, it would be crystal clear that (unlike in ovo angiogenesis) the tube formation of HUVECs is AKT-dependent, and PAK1-independent, as is the survival of all normal cells.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, if in ovo angiogenesis depends on either PAK1 or AKT (or both), both 15K and YM155 could inhibit the embryonic angiogenesis. So far it is most likely that tube formation of HUVECS depends solely on PAK1 (19,20), while their survival depends mainly on AKT (21). Thus, the most likely reason why YM155 causes their death and inhibits their tube formation, but 15K fails is that HUVECs simply rejects 15K.…”

Section: Discussionmentioning

confidence: 99%

Both triazolyl ester of ketorolac (15K) and YM155 inhibit the embryonic angiogenesis <i>in ovo</i> (fertilized eggs) <i>via</i> their common PAK1-survivin/VEGF signaling pathway

Ahn

Bae

Jeong

et al. 2017

DD&T

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Chemical composition and pharmacological properties of Macaranga‐type Pacific propolis: A review

Shahinozzaman

Obanda

Tawata

2020

Phytotherapy Research

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Propolis, a resinous substance, is collected from plants and processed by honeybees to seal holes and cracks in beehives, protecting them from microbial infection. Based on the plant source and geographical location, propolis is categorized into seven groups. Of these, Pacific propolis, found in the Pacific islands, originates from Macaranga spp. and is, therefore, known as Macaranga‐type Pacific propolis. Okinawa propolis and Taiwanese propolis, which are both Macaranga‐type propolis, are rich in prenylated flavonoids from the same botanical source, Macaranga tanarius, and are used locally as traditional remedies. They are reported to have a wide range of pharmacological benefits, including antioxidant, anti‐inflammation, antimicrobial, anticancer, antidiabetic, anti‐Alzheimer's, anti‐melanogenic, and longevity‐extending effects. However, not much is known about their mode of action, and recently, the extract of Okinawa propolis and its major prenylated flavonoids were found to selectively inhibit the oncogenic kinase, p21‐activated kinase 1 (PAK1). PAK1 enables cross‐talking among several signaling pathways, causing many diseases/disorders. The existing results reviewed here support the use of Macaranga‐type Pacific propolis for the effective development of safe herbal drugs and functional foods. Furthermore, its mode of action by modulating PAK1 can be explored, and the geographical and seasonal effects on its chemistry and biology, and its pharmacokinetics and toxicology should be studied as well.

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Frondoside A from sea cucumber and nymphaeols from Okinawa propolis: Natural anti-cancer agents that selectively inhibit PAK1 <i>in vitro </i>

Cited by 53 publications

References 13 publications

Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway

Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway

Both triazolyl ester of ketorolac (15K) and YM155 inhibit the embryonic angiogenesis <i>in ovo</i> (fertilized eggs) <i>via</i> their common PAK1-survivin/VEGF signaling pathway

Chemical composition and pharmacological properties of Macaranga‐type Pacific propolis: A review

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