This year a group at ISU in Louisiana found that Curcumin blocks the Raptor-TOR
(target of rapamycin) interaction which is essential for the activation
of TOR. The kinase TOR is abnormally activated when the tumor suppressors, TSC1 or
TSC2, dysfunction. The rare but formidable tumors associated with TSC (tuberous
sclerosis), where TSC1 or TSC2 dysfunctions, require TOR for their growth.
In animal experiments anti-TOR drugs such as rapamycin could suppress the
growth of TSC tumors, but none of these anti-TOR drugs is available on the
market as yet. However, the natural anti-cancer product "Curcumin" could
be potentially useful for the treatment of TSC, if its bioavailablity is
dramatically improved by either liposome, CD or propolis in the future, as
mentioned before.
Furthermore, two US groups, at Memorial Sloan-Kettering Cancer Center in
New York and MGH in Boston, reported recently that dysfunction of Merlin,
the NF2 gene product, which is the cause of NF2 tumors, also leads to the abnormal
activation of TOR. We found several years ago that Merlin is a direct PAK1
inhibitor (Hirokawa, Y. et al, 2004). It still remains to be clarified whether
the abnormal activation of TOR is through the kinase PAK1, which is abnormally
activated by the dysfunction of Merlin. Nevertheless, this finding suggests
that "Curcumin" could suppress the growth of NF2 tumors by at least two
ways, inactivating both PAK1 and TOR.
In this context, it would be of great interest to note that the tumor suppressor
"FOXO"/Daf-16 in a tiny nematode called C. elegans blocks the expression
of "Raptor", thereby inactivating "TOR". This potentially interesting finding
was reported in 2004 by Don Riddle's group at University of Missouri. Furthermore,
we recently found that the kinase PAK1 inactivates "FOXO" in this worm.
Thus, natural anti-PAK1 products such as Bio 30 and "Curcumin" would inactivate
"TOR" by reactivating "FOXO" at least in this worm. It would be certainly
worth testing whether this remains true with mammals, too.
To be continued
Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S. (2009).
Curcumin disrupts the Mammalian target of rapamycin-raptor complex.
Cancer Res. 69, 1000-8.
Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer Center,
Louisiana State University Health Sciences Center, Shreveport, Louisiana
71130-3932, USA.
Curcumin (diferuloylmethane), a polyphenol natural product of the plant
Curcuma longa, is undergoing early clinical trials as a novel anticancer
agent. However, the anticancer mechanism of curcumin remains to be elucidated.
Recently, we have shown that curcumin inhibits phosphorylation of p70 S6
kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein
1 (4E-BP1), two downstream effector molecules of the mammalian target of
rapamycin complex 1 (mTORC1) in numerous cancer cell lines. This study was
designed to elucidate the underlying mechanism. We observed that curcumin
inhibited mTORC1 signaling not by inhibition of the upstream kinases, such
as insulin-like growth factor 1 receptor (IGF-IR) and phosphoinositide-dependent
kinase 1 (PDK1). Further, we found that curcumin inhibited mTORC1 signaling
independently of protein phosphatase 2A (PP2A) or AMP-activated protein kinase
AMPK-tuberous sclerosis complex (TSC). This is evidenced by the findings
that curcumin was able to inhibit phosphorylation of S6K1 and 4E-BP1 in
the cells pretreated with PP2A inhibitor (okadaic acid) or AMPK inhibitor
(compound C), or in the cells expressing dominant-negative (dn) PP2A, shRNA
to PP2A-A subunit, or dn-AMPKalpha. Curcumin did not alter the TSC1/2 interaction.
Knockout of TSC2 did not affect curcumin inhibition of mTOR signaling.
Finally, we identified that
curcumin was able to dissociate raptor from mTOR, leading to inhibition
of mTORC1 activity. Therefore, our data indicate that curcumin may represent
a new class of mTOR inhibitor.
Lopez-Lago MA, Okada T, Murillo MM, Socci N, Giancotti FG. (2009)
Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates
integrin-dependent mTORC1 signaling.
Mol Cell Biol. 29, 4235-49.
Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial
Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA.
Integrin signaling promotes, through PAK1, phosphorylation and inactivation
of the tumor suppressor merlin, thus removing a block to mitogenesis in
normal cells. However, the biochemical function of merlin and the effector
pathways critical for the pathogenesis of malignant mesothelioma and other
NF2-related malignancies are not known. We report that integrin-specific
signaling promotes activation of mTORC1 and cap-dependent mRNA translation.
Depletion of merlin rescues mTORC1 signaling in cells deprived of anchorage
to a permissive extracellular matrix, suggesting that integrin signaling
controls mTORC1 through inactivation of merlin.
This signaling pathway controls translation of the cyclin D1 mRNA and, thereby,
cell cycle progression. In addition, it promotes cell survival. Analysis
of a panel of malignant mesothelioma cell lines reveals a strong correlation
between loss of merlin and activation of mTORC1.
Merlin-negative lines are sensitive to the growth-inhibitory effect of rapamycin,
and the expression of recombinant merlin renders them partially resistant
to rapamycin. Conversely, depletion of merlin restores rapamycin sensitivity
in merlin-positive lines. These results indicate that integrin-mediated
adhesion promotes mTORC1 signaling through the inactivation of merlin. Furthermore,
they reveal that merlin-negative mesotheliomas display unregulated mTORC1
signaling and are sensitive to rapamycin, thus providing a preclinical rationale
for prospective, biomarker-driven clinical studies of mTORC1 inhibitors
in these tumors.
2009年7月20日
Curcumin could cure both NF2 and TSC (tuberous sclerosis)
by "double" punches, knocking out PAK1 and TOR
2009年7月19日
"Combination" Therapy of PAK1-dependent Cancers and NF
by Two Inexpensive Natural Products, Bio 30 and Curcumin
NF (neurofibromatosis) tumors and 70% of human cancers require the oncogenic
kinase PAK1 for their growth. We have recently shown that Bio 30, the CAPE
(caffeic acid phenethyl ester) -rich extract of NZ (New Zealand) propolis
almost completely suppresses the growth of NF tumors, glioma, pancreatic
and breast cancer xenografts in mice. Another natural product called curcumin
was also known to block this kinase somehow. This summer Feng Li's group
at China Medical School reported that curcumin inactivates PAK1, at least
in part by down-regulating the Tyr-kinase ErbB2/HER2 (for detail, see the
abstract below). Several years ago we have shown that both ErbB1 (EGF receptor)
and ErbB2 are required for PAK1 activation (Hong He et al, 2001).
The major problem of curcumin alone for clinical application is its poor
bioavailability (mainly due to its water-insolubility) as previously discussed.
In the future, liposome or CD (cyclodextrin) could be used to solubilize
curcumin for clinical application. Interestingly, CAPE alone shares the same
problem. However, if CAPE is taken with several other anti-cancer polyphenols
in CAPE-based propolis extracts such as Bio 30, both its bioavailability
and anti-cancer potential are dramatically (over 600 times) improved (Maria
Demestre et al, 2009). Considering this finding, it would be worth to combine
curcumin and Bio 30 not only for improving the bioavailability of curcumin,
but also for creating its potential synergy with CAPE and several other
anti-cancer ingredients such as pinocembrin (PIN) in Bio 30.
Cancer Biol Ther. 2009 Jul 13;8(14).
Curcumin suppresses proliferation and invasion in human gastric cancer cells
by downregulation of PAK1 activity and cyclin D1 expression.
Cai XZ, Wang J, Li XD, Wang GL, Liu FN, Cheng MS, Li F.
Department of Cell Biology, Key Laboratory of Cell Biology of Ministry of
Public Health of China, China Medical University, Shenyang, China.
Curcumin (diferuloylmethane), is a natural chemopreventive agent known to
inhibit the proliferation of several cancer cell lines. It has been previously
demonstrated that curcumin is a potent inhibitor of EGF-receptor (EGFR)
tyrosine kinase, but its inhibitive effect on PAK1, a downstream protein
of EGFR, has not been defined. In this paper
we found that curcumin repressed the expression of HER2 and inhibited the
kinase activity of PAK1 without affecting its expression. Silencing HER2
in gastric cancer cells showed that even if PAK1 activity was transiently
strengthened by EGF, curcumin still had a strong inhibitive effect. It should
be emphasized that kinase assay in vitro showed that curcumin could act as
an ATP-competitive inhibitor, which was supported by computer-aided molecular
modeling. Curcumin also downregulated the mRNA and the protein expression
of cyclin D1 and suppressed transition of the cells from G(1) to S phase.
Therefore, curcumin inhibited the proliferation and invasion of gastric
cancer cells. Overall, these results provided novel insights into the mechanisms
of curcumin inhibition of gastric cancer cell growth and potential therapeutic
strategies for gastric cancer.
kinase PAK1 for their growth. We have recently shown that Bio 30, the CAPE
(caffeic acid phenethyl ester) -rich extract of NZ (New Zealand) propolis
almost completely suppresses the growth of NF tumors, glioma, pancreatic
and breast cancer xenografts in mice. Another natural product called curcumin
was also known to block this kinase somehow. This summer Feng Li's group
at China Medical School reported that curcumin inactivates PAK1, at least
in part by down-regulating the Tyr-kinase ErbB2/HER2 (for detail, see the
abstract below). Several years ago we have shown that both ErbB1 (EGF receptor)
and ErbB2 are required for PAK1 activation (Hong He et al, 2001).
The major problem of curcumin alone for clinical application is its poor
bioavailability (mainly due to its water-insolubility) as previously discussed.
In the future, liposome or CD (cyclodextrin) could be used to solubilize
curcumin for clinical application. Interestingly, CAPE alone shares the same
problem. However, if CAPE is taken with several other anti-cancer polyphenols
in CAPE-based propolis extracts such as Bio 30, both its bioavailability
and anti-cancer potential are dramatically (over 600 times) improved (Maria
Demestre et al, 2009). Considering this finding, it would be worth to combine
curcumin and Bio 30 not only for improving the bioavailability of curcumin,
but also for creating its potential synergy with CAPE and several other
anti-cancer ingredients such as pinocembrin (PIN) in Bio 30.
Cancer Biol Ther. 2009 Jul 13;8(14).
Curcumin suppresses proliferation and invasion in human gastric cancer cells
by downregulation of PAK1 activity and cyclin D1 expression.
Cai XZ, Wang J, Li XD, Wang GL, Liu FN, Cheng MS, Li F.
Department of Cell Biology, Key Laboratory of Cell Biology of Ministry of
Public Health of China, China Medical University, Shenyang, China.
Curcumin (diferuloylmethane), is a natural chemopreventive agent known to
inhibit the proliferation of several cancer cell lines. It has been previously
demonstrated that curcumin is a potent inhibitor of EGF-receptor (EGFR)
tyrosine kinase, but its inhibitive effect on PAK1, a downstream protein
of EGFR, has not been defined. In this paper
we found that curcumin repressed the expression of HER2 and inhibited the
kinase activity of PAK1 without affecting its expression. Silencing HER2
in gastric cancer cells showed that even if PAK1 activity was transiently
strengthened by EGF, curcumin still had a strong inhibitive effect. It should
be emphasized that kinase assay in vitro showed that curcumin could act as
an ATP-competitive inhibitor, which was supported by computer-aided molecular
modeling. Curcumin also downregulated the mRNA and the protein expression
of cyclin D1 and suppressed transition of the cells from G(1) to S phase.
Therefore, curcumin inhibited the proliferation and invasion of gastric
cancer cells. Overall, these results provided novel insights into the mechanisms
of curcumin inhibition of gastric cancer cell growth and potential therapeutic
strategies for gastric cancer.
2009年7月13日
OSU-03012, the "Synthetic" Anti-PAK1 Drug,
Blocks the Growth of NF2 Tumor Xenografts in Mice.
In 2007 a group led by Matthew Ringel at OSU (Ohio State University) found
that a synthetic compound called OSU-03012 selectively inhibits PAK1 in
vitro with IC50 around 1 micro M, and blocks the growth of several thyroid
cancer cell lines. In other words thyroid cancer is among PAK1-depenent
cancers. This compound is a derivative of the cyclooxygenese-2 inhibitor
"celecoxib", and was initially developed as a PDK1 inhibitor by Ching-Shih Chen's
group at OSU in 2004. It eventually inactivates another kinase AKT
by inhibiting the kinase PDK1. However, since it inhibits the growth of
PAK1-dependent (and AKT-independent) cancer cell lines such as PC-3 (PTEN-deficient
prostate cancer) and pancreatic cancer cells, it had been suggested that
OSU-03012 might block the kinase PAK1. In 2009 OSU-03012 (200 mg/kg, daily)
was found by Long-Sheng Chang's group at OSU to suppress the growth of NF2-deficient tumors
(Schwannoma) xenografts in mice by more than 50% (for detail, see the abstract below).
It should be worth to point it out that like ARC (Artepillin C) from Brazilian
green propolis, OSU-03012 is among the first single chemical drugs that
were shown to block the growth of NF2 tumors in vivo, although Bio 30
(100 mg/kg, twice a week) a mixture of several anti-cancer ingredients
including CAPE, was proven to block completely the growth of NF2 tumors in vivo, and is inexpensively available
on the market. If OSU-03012 is successful in the time and money-consuming
clinical trials for these PAK1-dependent cancers and NF tumors, this "synthetic"
compound would become available on the market in a decade or so... Hope
(unlike FK228) this drug can pass BBB (blood brain barrier) so that it works
on formidable brain tumors such as glioma and NF2 tumors.
Eur J Cancer. 2009 Jun; 45(9):1709-20
Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1
inhibitor, on vestibular schwannoma and malignant schwannoma cells.
Lee TX, Packer MD, Huang J, Akhmametyeva EM, Kulp SK, Chen CS, Giovannini
M, Jacob A, Welling DB, Chang LS.
Department of Otolaryngology, The Ohio State University College of Medicine,
Center for Childhood Cancer, The Research Institute at Nationwide Children's
Hospital, Columbus, OH, USA.
BACKGROUND: Vestibular schwannomas (VS) frequently express high levels of
activated AKT. Small-molecule inhibitors of AKT signalling may have therapeutic
potential in suppressing the growth of benign VS and malignant schwannomas.
METHOD: Primary VS and Schwann cells, human malignant schwannoma HMS-97
cells and mouse Nf2(-/-) Schwann cells and schwannoma cells were prepared
to investigate the growth inhibitory and anti-tumour activities of OSU-03012,
a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent
kinase-1. Cell proliferation assays, apoptosis, Western blot, in vivo xenograft
analysis using SCID mice and immunohistochemistry were performed.
RESULTS: OSU-03012 inhibited cell proliferation more effectively in both
VS and HMS-97 cells than in normal human Schwann cells. The IC5) of OSU-03012
at 48h was approximately 3 micro M for VS cells and HMS-97 cells, compared
with the IC(50) of greater than 12 micro M for human (normal) Schwann cells.
Similarly, mouse Nf2(-/-) schwannoma and Nf2(-/-) Schwann cells were more
sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann
cells and mouse schwannoma cells established from transgenic mice carrying
the NF2 promoter-driven SV40 T-antigen gene. Like VS cells, malignant schwannoma
HMS-97 cells expressed high levels of activated AKT. OSU-03012 induced apoptosis
in both VS and HMS-97 cells and caused a marked reduction of AKT phosphorylation
at both the Ser-308 and Thr-473 sites in a dose-dependent manner.
In vivo xenograft analysis showed that OSU-03012 was well tolerated and
inhibited the growth of HMS-97 schwannoma xenografts by 55% after 9 weeks
of oral treatment. The anti-tumour activity correlated with reduced AKT
phosphorylation.
CONCLUSION: OSU-03012 is a potential chemotherapeutic agent for VS and malignant
schwannomas.
that a synthetic compound called OSU-03012 selectively inhibits PAK1 in
vitro with IC50 around 1 micro M, and blocks the growth of several thyroid
cancer cell lines. In other words thyroid cancer is among PAK1-depenent
cancers. This compound is a derivative of the cyclooxygenese-2 inhibitor
"celecoxib", and was initially developed as a PDK1 inhibitor by Ching-Shih Chen's
group at OSU in 2004. It eventually inactivates another kinase AKT
by inhibiting the kinase PDK1. However, since it inhibits the growth of
PAK1-dependent (and AKT-independent) cancer cell lines such as PC-3 (PTEN-deficient
prostate cancer) and pancreatic cancer cells, it had been suggested that
OSU-03012 might block the kinase PAK1. In 2009 OSU-03012 (200 mg/kg, daily)
was found by Long-Sheng Chang's group at OSU to suppress the growth of NF2-deficient tumors
(Schwannoma) xenografts in mice by more than 50% (for detail, see the abstract below).
It should be worth to point it out that like ARC (Artepillin C) from Brazilian
green propolis, OSU-03012 is among the first single chemical drugs that
were shown to block the growth of NF2 tumors in vivo, although Bio 30
(100 mg/kg, twice a week) a mixture of several anti-cancer ingredients
including CAPE, was proven to block completely the growth of NF2 tumors in vivo, and is inexpensively available
on the market. If OSU-03012 is successful in the time and money-consuming
clinical trials for these PAK1-dependent cancers and NF tumors, this "synthetic"
compound would become available on the market in a decade or so... Hope
(unlike FK228) this drug can pass BBB (blood brain barrier) so that it works
on formidable brain tumors such as glioma and NF2 tumors.
Eur J Cancer. 2009 Jun; 45(9):1709-20
Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1
inhibitor, on vestibular schwannoma and malignant schwannoma cells.
Lee TX, Packer MD, Huang J, Akhmametyeva EM, Kulp SK, Chen CS, Giovannini
M, Jacob A, Welling DB, Chang LS.
Department of Otolaryngology, The Ohio State University College of Medicine,
Center for Childhood Cancer, The Research Institute at Nationwide Children's
Hospital, Columbus, OH, USA.
BACKGROUND: Vestibular schwannomas (VS) frequently express high levels of
activated AKT. Small-molecule inhibitors of AKT signalling may have therapeutic
potential in suppressing the growth of benign VS and malignant schwannomas.
METHOD: Primary VS and Schwann cells, human malignant schwannoma HMS-97
cells and mouse Nf2(-/-) Schwann cells and schwannoma cells were prepared
to investigate the growth inhibitory and anti-tumour activities of OSU-03012,
a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent
kinase-1. Cell proliferation assays, apoptosis, Western blot, in vivo xenograft
analysis using SCID mice and immunohistochemistry were performed.
RESULTS: OSU-03012 inhibited cell proliferation more effectively in both
VS and HMS-97 cells than in normal human Schwann cells. The IC5) of OSU-03012
at 48h was approximately 3 micro M for VS cells and HMS-97 cells, compared
with the IC(50) of greater than 12 micro M for human (normal) Schwann cells.
Similarly, mouse Nf2(-/-) schwannoma and Nf2(-/-) Schwann cells were more
sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann
cells and mouse schwannoma cells established from transgenic mice carrying
the NF2 promoter-driven SV40 T-antigen gene. Like VS cells, malignant schwannoma
HMS-97 cells expressed high levels of activated AKT. OSU-03012 induced apoptosis
in both VS and HMS-97 cells and caused a marked reduction of AKT phosphorylation
at both the Ser-308 and Thr-473 sites in a dose-dependent manner.
In vivo xenograft analysis showed that OSU-03012 was well tolerated and
inhibited the growth of HMS-97 schwannoma xenografts by 55% after 9 weeks
of oral treatment. The anti-tumour activity correlated with reduced AKT
phosphorylation.
CONCLUSION: OSU-03012 is a potential chemotherapeutic agent for VS and malignant
schwannomas.
2009年7月7日
PAK1-LC8 (Dynein Light Chain) Interaction
Required for Nuclear Import of PAK1.
PAK1 is an oncogenic Ser/Thr kinase which is activated by several cytoplasmic
proteins such as GTPases (Rac and CDC42), SH3 adaptor proteins (PIX and
NCK), and Tyr-kinase (ETK). This kinase is required for the growth of more
than 70% of human cancers, including breast and prostate cancers, as well
as formidable brain tumors such as glioma and NF (neurofibromatosis) tumors.
Recently John Williams' group at Thomas Jefferson University in Philadelphia
found that Dynein Light Chain (LC8) also binds residues 212-222 of PAK1
which is adjacent to the essential NLS (nuclear localization site, residues
243-245), and their interaction leads to the dimerization of PAK1 through
NLS and is required for the EGF-induced nuclear import of the cytoplasmic
PAK1 in MCF-7, an estrogen-dependent breast cancer cell line. Since PAK1
phosphorylates the nuclear estrogen receptor (ER) at Ser 305 for the ER
activation which leads to the estrogen-dependent malignant growth of this
cell line, LC8 appears to contribute to the oncogenicity of PAK1 by nuclear
import.
PLoS One. 2009 Jun 26;4(6):e6025
Interaction with LC8 is required for Pak1 nuclear import and is indispensable
for zebrafish development.
Lightcap CM, Kari G, Arias-Romero LE, Chernoff J, Rodeck U, Williams, John
C.
Department of Biochemistry and Molecular Biology, Thomas Jefferson University,
Philadelphia, PA, USA.
Pak1 is a serine/threonine kinase implicated in regulation of cell motility
and survival and in malignant transformation of mammary epithelial cells.
In addition, the dynein light chain, LC8, has been described to cooperate
with Pak1 in malignant transformation of breast cancer cells. Pak1 itself
may aid breast cancer development by phosphorylating nuclear proteins, including
estrogen receptor alpha. Recently, we showed that the LC8 binding site on
Pak1 is adjacent to the nuclear localization sequence (NLS) required for
Pak1 nuclear import.
Here, we demonstrate that the LC8-Pak1 interaction is necessary for epidermal
growth factor (EGF)-induced nuclear import of Pak1 in MCF-7 cells, and that
this event is contingent upon LC8-mediated Pak1 dimerization. In contrast,
Pak2, which lacks an LC8 binding site but contains a nuclear localization
sequence identical to that in Pak1, remains cytoplasmic upon EGF stimulation
of MCF-7 cells.
Furthermore, we show that severe developmental defects in zebrafish embryos
caused by morpholino injections targeting Pak are partially rescued by co-injection
of wild-type human Pak1, but not by co-injection of mutant Pak1 mRNA disrupting
either the LC8 binding or the NLS site.
Collectively, these results suggest that LC8 facilitates nuclear import
of Pak1 and that this function is indispensable during vertebrate development.
proteins such as GTPases (Rac and CDC42), SH3 adaptor proteins (PIX and
NCK), and Tyr-kinase (ETK). This kinase is required for the growth of more
than 70% of human cancers, including breast and prostate cancers, as well
as formidable brain tumors such as glioma and NF (neurofibromatosis) tumors.
Recently John Williams' group at Thomas Jefferson University in Philadelphia
found that Dynein Light Chain (LC8) also binds residues 212-222 of PAK1
which is adjacent to the essential NLS (nuclear localization site, residues
243-245), and their interaction leads to the dimerization of PAK1 through
NLS and is required for the EGF-induced nuclear import of the cytoplasmic
PAK1 in MCF-7, an estrogen-dependent breast cancer cell line. Since PAK1
phosphorylates the nuclear estrogen receptor (ER) at Ser 305 for the ER
activation which leads to the estrogen-dependent malignant growth of this
cell line, LC8 appears to contribute to the oncogenicity of PAK1 by nuclear
import.
PLoS One. 2009 Jun 26;4(6):e6025
Interaction with LC8 is required for Pak1 nuclear import and is indispensable
for zebrafish development.
Lightcap CM, Kari G, Arias-Romero LE, Chernoff J, Rodeck U, Williams, John
C.
Department of Biochemistry and Molecular Biology, Thomas Jefferson University,
Philadelphia, PA, USA.
Pak1 is a serine/threonine kinase implicated in regulation of cell motility
and survival and in malignant transformation of mammary epithelial cells.
In addition, the dynein light chain, LC8, has been described to cooperate
with Pak1 in malignant transformation of breast cancer cells. Pak1 itself
may aid breast cancer development by phosphorylating nuclear proteins, including
estrogen receptor alpha. Recently, we showed that the LC8 binding site on
Pak1 is adjacent to the nuclear localization sequence (NLS) required for
Pak1 nuclear import.
Here, we demonstrate that the LC8-Pak1 interaction is necessary for epidermal
growth factor (EGF)-induced nuclear import of Pak1 in MCF-7 cells, and that
this event is contingent upon LC8-mediated Pak1 dimerization. In contrast,
Pak2, which lacks an LC8 binding site but contains a nuclear localization
sequence identical to that in Pak1, remains cytoplasmic upon EGF stimulation
of MCF-7 cells.
Furthermore, we show that severe developmental defects in zebrafish embryos
caused by morpholino injections targeting Pak are partially rescued by co-injection
of wild-type human Pak1, but not by co-injection of mutant Pak1 mRNA disrupting
either the LC8 binding or the NLS site.
Collectively, these results suggest that LC8 facilitates nuclear import
of Pak1 and that this function is indispensable during vertebrate development.
2009年6月19日
「シクロデキストリン」の食品や医薬への応用
シクロデキストリンとは、環状オリゴ糖で、分子の外側は親水性で、内側は疎水
性である。従って、疎水性の低分子物質を、その分子の内側に取り込み、水溶化
しうる働きを持つ。
詳しくは、ブドウ糖が連なってできたオリゴ糖の両端が繋がり輪の形になってお
り、構造的には、フタと底のないカップのような分子である。そして、この空洞
部分に様々な分子を取り込んだり（包接）、逆に取り込んだ分子を条件に応じて
中からゆっくりと放出させたり（徐放）といった作用を示めす。この性質を応用
して様々な分野でいろいろな商品に利用されている。ちなみに、シクロデキスト
リンは、ジャガイモやトウモロコシ等のデンプンを原材料としている。
具体的な商品化の一例としては、臭い成分を取り込む作用を活かした消臭剤への
活用やカテキンやイソフラボンなどの有効成分の苦み渋みを低減する目的で飲料
への利用、また卵黄・バター等からコレステロールの除去効果を利用した食品分
野への応用などがある。さらに、機能性食品やサプリメントへの応用として、例
えば、コエンザイムQ10など難水溶性のため吸収されにくい機能性成分を、シクロ
デキストリンにより水溶性化させ吸収を高めるといった利用もなされている。
我々が最近興味をもち始めたのは、シクロデキストンをプロポリス、花椒エキス、
クルクミン、イバメクチン、納豆のビタミンＫ２（メナキノンー７）など難水溶
性の天然制癌（ＰＡＫ遮断) 物質の水溶化に利用して、その体内への吸収を促進
するばかりではなく、その独特の苦味や匂いを軽減する働きを活用することにあ
る。さらに、シクロデキストンは、その空洞内に低分子だけを選択的に取り込む
ので、蛋白や多糖類などの高分子をも含む酵母や植物エキスから、低分子の抗癌
物質、例えば「ピノセンブリン」だけを選別／抽出しうるツールとしても利用できる
可能性があるからだ。
数年前、シクロケム (社長、寺尾啓二) が岡山理科大学との共同研究で、天然の
アルファー・シクロデキストン（ａｌｐｈａーＣＤ、２％）によるクルクミンの水溶化(最大溶解度、
０。３ mg/ml) に成功したという報告が出ている。 動物実験で、この
ＣＤークルクミンが実際に癌やＮＦ腫瘍の増殖抑制に有効というデータはまだ出
ていないようだが、例えば、担癌マウス (体重２０ｇ）にこの溶液を週２回ずつ、
最大０。４ ml (つまり、６ ｍｇ／ｋｇ）腹腔注射して、有意な効果 (例えば、
５０％以上の増殖阻害) が得られれば、この新しいクルクミン製剤による癌治療
の早期実用化が有望となろう。なお、クルクミンの水溶化は、リポソームやベー
タＣＤ誘導体でも最近、米国やインドでそれぞれ成功しているが、これらの可溶
化剤（後者）は天然物ではないので、治療への実用化（各々の政府から市販許可
を得る）には、まだ時間が相当かかるだろう。
参考までに、リポソームによる包接の場合を一例としてあげると、担癌マウスに
クリクミン投与 (２０ ｍｇ／ｋｇ) で、すいぞう癌の増殖が５０％以上抑制される
という結果が、テキサスのＭＤアンダーソン癌センターから、つい最近報告されている。
Anticancer Res. 2009 Jun; 29: 1895-9.
Determination of minimum effective dose and optimal dosing schedule
for liposomal curcumin in a xenograft human pancreatic cancer model.
Mach CM, Mathew L, Mosley SA, Kurzrock R, Smith JA.
Department of Gynecologic Oncology, Division of Surgery, P.O. Box
301439-UNIT 1362, Houston, Texas 77230-1439, U.S.A.
jasmith@mdanderson.org
BACKGROUND: Curcumin is a food chemical present in tumeric (Curcuma longa)
that has pharmacological activity to suppress carcinogenesis and inhibits
multiple signaling pathways such as nuclear factor kappaB (NF-kappaB),
cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8). Oral curcumin has poor oral
bioavailability limiting its clinical activity;
however, a patent pending liposomal formulation of curcumin was developed
to improve drug delivery and has demonstrated activity in multiple cancers.
This study was designed to determine the minimum effective dose (MED)
as well as the optimal dosing schedule of liposomal curcumin
in a xenograft mouse model of human pancreatic cancer.
MATERIALS AND METHODS: The MED determination and optimal schedule was evaluated
in female athymic nude mice injected subcutaneously with MiaPaCa-2 cells.
Dosing was initiated at an average tumor size of 5mm. For the MED, mice
were treated with the following dose levels of liposomal curcumin: no treatment,
liposome only, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg
given by tail vein injection three times weekly for 28 days. For the optimum
dosing schedule, three additional schedules were evaluated and compared
to the control of three times weekly; daily (five days per week), every
four days, and weekly for 28 days. All mice were weighed and tumor measurements
taken three times weekly to evaluate toxicity and efficacy.
RESULTS: The 20 mg/kg dose had the greatest decrease in tumor growth at
52% decrease in tumor growth when compared to no treatment control mice.
MED was determined to be 20 mg/kg and was used for the optimal dosing schedule
determination. Daily dosing and three times per week dosing had greater
inhibition of tumor growth with no discernable difference than once weekly
or every 4 day dosing. No toxicity was observed at any dose or schedule.
CONCLUSION: The MED for liposomal curcumin is 20 mg/kg given once daily
three times per week to achieve optimal tumor growth inhibition. This was
dose recommended for additional preclinical studies to define safety and
tolerability of liposomal curcumin in rat and dog models.
続く
性である。従って、疎水性の低分子物質を、その分子の内側に取り込み、水溶化
しうる働きを持つ。
詳しくは、ブドウ糖が連なってできたオリゴ糖の両端が繋がり輪の形になってお
り、構造的には、フタと底のないカップのような分子である。そして、この空洞
部分に様々な分子を取り込んだり（包接）、逆に取り込んだ分子を条件に応じて
中からゆっくりと放出させたり（徐放）といった作用を示めす。この性質を応用
して様々な分野でいろいろな商品に利用されている。ちなみに、シクロデキスト
リンは、ジャガイモやトウモロコシ等のデンプンを原材料としている。
具体的な商品化の一例としては、臭い成分を取り込む作用を活かした消臭剤への
活用やカテキンやイソフラボンなどの有効成分の苦み渋みを低減する目的で飲料
への利用、また卵黄・バター等からコレステロールの除去効果を利用した食品分
野への応用などがある。さらに、機能性食品やサプリメントへの応用として、例
えば、コエンザイムQ10など難水溶性のため吸収されにくい機能性成分を、シクロ
デキストリンにより水溶性化させ吸収を高めるといった利用もなされている。
我々が最近興味をもち始めたのは、シクロデキストンをプロポリス、花椒エキス、
クルクミン、イバメクチン、納豆のビタミンＫ２（メナキノンー７）など難水溶
性の天然制癌（ＰＡＫ遮断) 物質の水溶化に利用して、その体内への吸収を促進
するばかりではなく、その独特の苦味や匂いを軽減する働きを活用することにあ
る。さらに、シクロデキストンは、その空洞内に低分子だけを選択的に取り込む
ので、蛋白や多糖類などの高分子をも含む酵母や植物エキスから、低分子の抗癌
物質、例えば「ピノセンブリン」だけを選別／抽出しうるツールとしても利用できる
可能性があるからだ。
数年前、シクロケム (社長、寺尾啓二) が岡山理科大学との共同研究で、天然の
アルファー・シクロデキストン（ａｌｐｈａーＣＤ、２％）によるクルクミンの水溶化(最大溶解度、
０。３ mg/ml) に成功したという報告が出ている。 動物実験で、この
ＣＤークルクミンが実際に癌やＮＦ腫瘍の増殖抑制に有効というデータはまだ出
ていないようだが、例えば、担癌マウス (体重２０ｇ）にこの溶液を週２回ずつ、
最大０。４ ml (つまり、６ ｍｇ／ｋｇ）腹腔注射して、有意な効果 (例えば、
５０％以上の増殖阻害) が得られれば、この新しいクルクミン製剤による癌治療
の早期実用化が有望となろう。なお、クルクミンの水溶化は、リポソームやベー
タＣＤ誘導体でも最近、米国やインドでそれぞれ成功しているが、これらの可溶
化剤（後者）は天然物ではないので、治療への実用化（各々の政府から市販許可
を得る）には、まだ時間が相当かかるだろう。
参考までに、リポソームによる包接の場合を一例としてあげると、担癌マウスに
クリクミン投与 (２０ ｍｇ／ｋｇ) で、すいぞう癌の増殖が５０％以上抑制される
という結果が、テキサスのＭＤアンダーソン癌センターから、つい最近報告されている。
Anticancer Res. 2009 Jun; 29: 1895-9.
Determination of minimum effective dose and optimal dosing schedule
for liposomal curcumin in a xenograft human pancreatic cancer model.
Mach CM, Mathew L, Mosley SA, Kurzrock R, Smith JA.
Department of Gynecologic Oncology, Division of Surgery, P.O. Box
301439-UNIT 1362, Houston, Texas 77230-1439, U.S.A.
jasmith@mdanderson.org
BACKGROUND: Curcumin is a food chemical present in tumeric (Curcuma longa)
that has pharmacological activity to suppress carcinogenesis and inhibits
multiple signaling pathways such as nuclear factor kappaB (NF-kappaB),
cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8). Oral curcumin has poor oral
bioavailability limiting its clinical activity;
however, a patent pending liposomal formulation of curcumin was developed
to improve drug delivery and has demonstrated activity in multiple cancers.
This study was designed to determine the minimum effective dose (MED)
as well as the optimal dosing schedule of liposomal curcumin
in a xenograft mouse model of human pancreatic cancer.
MATERIALS AND METHODS: The MED determination and optimal schedule was evaluated
in female athymic nude mice injected subcutaneously with MiaPaCa-2 cells.
Dosing was initiated at an average tumor size of 5mm. For the MED, mice
were treated with the following dose levels of liposomal curcumin: no treatment,
liposome only, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg
given by tail vein injection three times weekly for 28 days. For the optimum
dosing schedule, three additional schedules were evaluated and compared
to the control of three times weekly; daily (five days per week), every
four days, and weekly for 28 days. All mice were weighed and tumor measurements
taken three times weekly to evaluate toxicity and efficacy.
RESULTS: The 20 mg/kg dose had the greatest decrease in tumor growth at
52% decrease in tumor growth when compared to no treatment control mice.
MED was determined to be 20 mg/kg and was used for the optimal dosing schedule
determination. Daily dosing and three times per week dosing had greater
inhibition of tumor growth with no discernable difference than once weekly
or every 4 day dosing. No toxicity was observed at any dose or schedule.
CONCLUSION: The MED for liposomal curcumin is 20 mg/kg given once daily
three times per week to achieve optimal tumor growth inhibition. This was
dose recommended for additional preclinical studies to define safety and
tolerability of liposomal curcumin in rat and dog models.
続く
2009年6月18日
"PIN-MITE": a new Pinocembrin (PIN)-rich health care product
Pinocembrin (PIN) content in Bio 30 is 11% (110 mg/g, dry weight), the highest
among propolis samples around the world. PIN is a flavonoid rich in pine
trees. A cluster of genes such as CHS and CHI for its biosynthesis was cloned
from red pine several years ago, and now it becomes possible to mass produce
PIN in E. coli or yeasts (S. cerevisiae or S. pombe), using glucose and
Phe as two major nutrient sources. We are planning to mass produce PIN in
yeast under the control of Hsp16 (heat-shock) gene promoter by heat shock
treatment, to make a new PIN-rich health care product called "PIN-Mite"
(anti-cancer/NF remedy or "elixir") as an alternative of Bio 30 or "Natto".
Why are we so interested in PIN? it has been known for some years that
like CAPE (caffeic acid phenethyl ester) , PIN is anti-inflammatory, suggesting
the possibility that it might block the kinase PAK1 which is essential for
inflammation, in particular calcium-release from mast cells. This year it
was reported by a Japanese group that like CAPE and ARC (artepillin C),
PIN blocks angiogenesis which also requires PAK1. Since both CAPE and ARC,
the major anti-cancer ingredients in propolis, block PAK1, it is almost
certain that PIN also blocks the oncogenic PAK1 signaling somehow. We are
asking a friend of mine in Japan to confirm this notion directly in cell
culture, by testing the effect of PIN on p-Raf 1 (Ser 338) which is a direct
indicator of PAK1's kinase activity.
However, like CAPE and ARC, PIN is water-insoluble (therefore its bioavailability
would be poor if alone). Lipids in propolis solubilize these water-insoluble
PAK1-blockers. That is a reason why CAPE in propolis such as Bio 30 is far
better (more effective) than CAPE alone in vivo. However, there must be
another reason. Bio 30 is 600 times more effective than CAPE alone in vitro
(cell culture). Bio 30 contains several polyphenols/flavonoids, in addition
to CAPE: among them PIN is the most abundant (110 mg/g), almost 10 times
more than CAPE (only 12 mg/g). Thus, PIN and several other anti-cancer flavonoids
in Bio 30 must work synergestically with CAPE to suppress the growth of
PAK1-dependent cancers/NF.
An OZ scientist developed a unique salty yeast extract called "Vegemite"
as a spread in 1922. It has been sold by a major food company called "Kraft"
. "Vegemite" for OZ school kids is equivalent to "peanuts butter" for US
counterparts. They are the most favourite spreads to make their lunch sandwiches
tasty. Well, can we make a hybrid of "Vegemite and PIN-rich yeast extract,
which we might call "PIN-MITE"? YES, WE CAN! Alternatively, can we make
another hybrid product of "Natto" and PIN-rich yeast extract? YES, WE CAN!
As previously mentioned, Natto is a traditional Japanese fermented sticky
soy-bean product, and the richest source of vitamin K2, in particular menaquinone-
7 (MK-7). Like PIN, MK-7 is most likely to block PAK1, and has been shown
to suppress the growth of PAK1-dependent cancers such as pancreatic and ovarian
cancers.
Since PAK1 shortens the life span, anti-PAK1 products in propolis such as
CAPE, ARC and PIN as well as MK-7 in Natto would prolong our life in good
health, protecting us from cancers, NF, inflammation such as asthma and
arthritis, and aging diseases such as AD (Alzheimer's).
Pearl S. Buck (1892-1973), the author of "Good Earth" and the 1938 Nobel
laureate in Literature for bridging the West and East cultures, once said:
a hybrid child is far better than each of his or her (more pure) parents,
because two different (complementary) set of genes cause a synergy. Barack
Obama has proved it at the 2008 US election. Better than the more Anglo-Saxon
(or WASP) candidates Hillary Clinton and John McCaine! Like PSB, Obama
understands both sides: East and West, Christian and Moslem, Poor and Rich,
Conservative and Liberal, Republican and Democrat, Old and Young. His vast
knowledge and tolerance is the major power for governing US and the rest
of our world. So his handsome picture (or PSB's young portrait) could be
used for the label of our new mighty spread "PIN-Mite" jars or bottles for
the world-wide promotion...
To be continued.
among propolis samples around the world. PIN is a flavonoid rich in pine
trees. A cluster of genes such as CHS and CHI for its biosynthesis was cloned
from red pine several years ago, and now it becomes possible to mass produce
PIN in E. coli or yeasts (S. cerevisiae or S. pombe), using glucose and
Phe as two major nutrient sources. We are planning to mass produce PIN in
yeast under the control of Hsp16 (heat-shock) gene promoter by heat shock
treatment, to make a new PIN-rich health care product called "PIN-Mite"
(anti-cancer/NF remedy or "elixir") as an alternative of Bio 30 or "Natto".
Why are we so interested in PIN? it has been known for some years that
like CAPE (caffeic acid phenethyl ester) , PIN is anti-inflammatory, suggesting
the possibility that it might block the kinase PAK1 which is essential for
inflammation, in particular calcium-release from mast cells. This year it
was reported by a Japanese group that like CAPE and ARC (artepillin C),
PIN blocks angiogenesis which also requires PAK1. Since both CAPE and ARC,
the major anti-cancer ingredients in propolis, block PAK1, it is almost
certain that PIN also blocks the oncogenic PAK1 signaling somehow. We are
asking a friend of mine in Japan to confirm this notion directly in cell
culture, by testing the effect of PIN on p-Raf 1 (Ser 338) which is a direct
indicator of PAK1's kinase activity.
However, like CAPE and ARC, PIN is water-insoluble (therefore its bioavailability
would be poor if alone). Lipids in propolis solubilize these water-insoluble
PAK1-blockers. That is a reason why CAPE in propolis such as Bio 30 is far
better (more effective) than CAPE alone in vivo. However, there must be
another reason. Bio 30 is 600 times more effective than CAPE alone in vitro
(cell culture). Bio 30 contains several polyphenols/flavonoids, in addition
to CAPE: among them PIN is the most abundant (110 mg/g), almost 10 times
more than CAPE (only 12 mg/g). Thus, PIN and several other anti-cancer flavonoids
in Bio 30 must work synergestically with CAPE to suppress the growth of
PAK1-dependent cancers/NF.
An OZ scientist developed a unique salty yeast extract called "Vegemite"
as a spread in 1922. It has been sold by a major food company called "Kraft"
. "Vegemite" for OZ school kids is equivalent to "peanuts butter" for US
counterparts. They are the most favourite spreads to make their lunch sandwiches
tasty. Well, can we make a hybrid of "Vegemite and PIN-rich yeast extract,
which we might call "PIN-MITE"? YES, WE CAN! Alternatively, can we make
another hybrid product of "Natto" and PIN-rich yeast extract? YES, WE CAN!
As previously mentioned, Natto is a traditional Japanese fermented sticky
soy-bean product, and the richest source of vitamin K2, in particular menaquinone-
7 (MK-7). Like PIN, MK-7 is most likely to block PAK1, and has been shown
to suppress the growth of PAK1-dependent cancers such as pancreatic and ovarian
cancers.
Since PAK1 shortens the life span, anti-PAK1 products in propolis such as
CAPE, ARC and PIN as well as MK-7 in Natto would prolong our life in good
health, protecting us from cancers, NF, inflammation such as asthma and
arthritis, and aging diseases such as AD (Alzheimer's).
Pearl S. Buck (1892-1973), the author of "Good Earth" and the 1938 Nobel
laureate in Literature for bridging the West and East cultures, once said:
a hybrid child is far better than each of his or her (more pure) parents,
because two different (complementary) set of genes cause a synergy. Barack
Obama has proved it at the 2008 US election. Better than the more Anglo-Saxon
(or WASP) candidates Hillary Clinton and John McCaine! Like PSB, Obama
understands both sides: East and West, Christian and Moslem, Poor and Rich,
Conservative and Liberal, Republican and Democrat, Old and Young. His vast
knowledge and tolerance is the major power for governing US and the rest
of our world. So his handsome picture (or PSB's young portrait) could be
used for the label of our new mighty spread "PIN-Mite" jars or bottles for
the world-wide promotion...
To be continued.
2009年6月10日
Opening a "PRC" (Propolis Research Center)?
Chemical composition of propolis varies from one sample to another, because
honey bees in different areas such as NZ (New Zealand) and Brazil collect
entirely different things from local flowers and trees to make their beehives.
For instance, regarding the major anti-cancer ingredients, NZ propolis
is rich in CAPE (caffeic acid phenethyl ester), while Brazilian green propolis
is rich in ARC (Artepillin C). However, all these propolis samples share
a common biological property. They are anti-bacterial, anti-viral, stimulate
immune system, and block the oncogenic kinase PAK1 which is not only essential
for the growth of more than 70% of human cancers including breast and prostate
cancers as well as NF (neurofibromatosis) tumors, but also shortens our
life span.
Thus, we are potentially interested in opening a unique propolis research
center (PRC) to develop the most potent propolis, which block PAK1 most
efficiently, by our own hands. We have recently developed an inexpensive
and quick in vivo bioassay system to quantify the anti-PAK1 (so-called "elixir
of life") activity of natural products such as propolis. The special strain
(CL2070) of a tiny transparent nematode called C. elegans contains an extra
chimeric gene called Hsp16:GFP which expresses GFP (green fluorescent protein)
under the control of the promoter of Hsp16 gene. GFP is derived from a
fluorescent jellyfish, and glows green when it is exposed to blue light.
This GFP technology was developed by the three 2008 Nobel laureates in Chemistry,
Osamu Shimomura, Martin Chalfie and Roger Tsien. Hsp16 gene produces a
heat shock protein which contributes to the prolonged life span. and heat
endurance (thermal resistance). This gene requires a transcription factor
called "FOXO" which is normally suppressed by the kinase PAK1. So when PAK1
in this worm is blocked by the treatment with propolis, FOXO would be highly
activated and consequently the promoter of Hsp16 gene is activated after
a brief heat-shock to induce the GFP production in this worm. The stronger
its anti-PAK1 activity, the brighter the worm glows.
Using this GFP nematode system, we could screen for the most potent propolis
sample. In both mouse and this worm systems, we have shown that Bio 30,
CAPE-based NZ propolis extract, is much more potent than GPE, ARC-based
Brazilian green propolis extract. In the future we would like to develop
a new propolis which is even far more potent than Bio 30, hopefully. For
this specific purpose, we are planning to open a PRC of our own, a new bee
farm where we grow both honey bees and several selected flowers to harvest
a unique propolis of our own, and determine which combination of flowers
would be the best source for the production of the most potent propolis.
To initiate such a pilot PRC, I shall start a bee farm at my own home garden,
which was recently bought in Brunswick West, outskirts of Melbourne, hopefully
in the near future, following the instruction of an e-book "Bee Keeping
for Beginners" or a paperback "The Backyard Beekeeper: An Absolute Beginner's Guide
to Keeping Bees in Your Yard and Garden"...
To be continued
honey bees in different areas such as NZ (New Zealand) and Brazil collect
entirely different things from local flowers and trees to make their beehives.
For instance, regarding the major anti-cancer ingredients, NZ propolis
is rich in CAPE (caffeic acid phenethyl ester), while Brazilian green propolis
is rich in ARC (Artepillin C). However, all these propolis samples share
a common biological property. They are anti-bacterial, anti-viral, stimulate
immune system, and block the oncogenic kinase PAK1 which is not only essential
for the growth of more than 70% of human cancers including breast and prostate
cancers as well as NF (neurofibromatosis) tumors, but also shortens our
life span.
Thus, we are potentially interested in opening a unique propolis research
center (PRC) to develop the most potent propolis, which block PAK1 most
efficiently, by our own hands. We have recently developed an inexpensive
and quick in vivo bioassay system to quantify the anti-PAK1 (so-called "elixir
of life") activity of natural products such as propolis. The special strain
(CL2070) of a tiny transparent nematode called C. elegans contains an extra
chimeric gene called Hsp16:GFP which expresses GFP (green fluorescent protein)
under the control of the promoter of Hsp16 gene. GFP is derived from a
fluorescent jellyfish, and glows green when it is exposed to blue light.
This GFP technology was developed by the three 2008 Nobel laureates in Chemistry,
Osamu Shimomura, Martin Chalfie and Roger Tsien. Hsp16 gene produces a
heat shock protein which contributes to the prolonged life span. and heat
endurance (thermal resistance). This gene requires a transcription factor
called "FOXO" which is normally suppressed by the kinase PAK1. So when PAK1
in this worm is blocked by the treatment with propolis, FOXO would be highly
activated and consequently the promoter of Hsp16 gene is activated after
a brief heat-shock to induce the GFP production in this worm. The stronger
its anti-PAK1 activity, the brighter the worm glows.
Using this GFP nematode system, we could screen for the most potent propolis
sample. In both mouse and this worm systems, we have shown that Bio 30,
CAPE-based NZ propolis extract, is much more potent than GPE, ARC-based
Brazilian green propolis extract. In the future we would like to develop
a new propolis which is even far more potent than Bio 30, hopefully. For
this specific purpose, we are planning to open a PRC of our own, a new bee
farm where we grow both honey bees and several selected flowers to harvest
a unique propolis of our own, and determine which combination of flowers
would be the best source for the production of the most potent propolis.
To initiate such a pilot PRC, I shall start a bee farm at my own home garden,
which was recently bought in Brunswick West, outskirts of Melbourne, hopefully
in the near future, following the instruction of an e-book "Bee Keeping
for Beginners" or a paperback "The Backyard Beekeeper: An Absolute Beginner's Guide
to Keeping Bees in Your Yard and Garden"...
To be continued
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