natural inhibitor of PI3K
 

about a year and a half ago, someone posted a question--were there natural inhibitors of PI3K. Several posted articles, but I just found this one which seems all the more timely as we have been discussing the different isoforms of CLA recently:
cis-9,trans-11-Conjugated linoleic acid down-regulates phorbol ester-induced NF-B activation and subsequent COX-2 expression in hairless mouse skin by targeting IB kinase and PI3K-Akt

Dal-Mi Hwang1, Joydeb Kumar Kundu1, Jun-Wan Shin1, Jung-Chul Lee1, Hyong Joo Lee2 and Young-Joon Surh1,*
1 National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy Seoul 151-742, South Korea
2 Department of Food Science and Technology, College of Agriculture and Life Sciences, Seoul National University Seoul 151-742, South Korea

*To whom correspondence should be addressed at: College of Pharmacy, Seoul National University, Shillim-dong, Kwanak-ku, Seoul 151-742, Korea. Tel: +82 2 880 7845; Fax: +82 2 874 9775; Email: surh@plaza.snu.ac.kr

Conjugated linoleic acid (CLA) has been reported to inhibit mouse skin carcinogenesis, particularly in the promotion stage, but underlying molecular mechanisms remain poorly understood. Since persistent induction of cyclooxygenase-2 (COX-2) is frequently implicated in carcinogenesis, we investigated the effect of cis-9,trans-11-CLA (9Z,11E-CLA) on the tumor promoter-induced COX-2 expression in HR-1 hairless mouse skin in vivo. Topical application of 9Z,11E-CLA caused significant inhibition of COX-2 expression at 6 h induced by 10 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) in HR-1 mouse skin. Since NF-B is known to regulate COX-2 gene expression, we determined the effect of 9Z,11E-CLA on TPA-induced activation of this transcription factor. Treatment of mouse skin with 9Z,11E-CLA reduced TPA-induced DNA binding as well as nuclear translocation of NF-B by blocking phosphorylation and subsequent degradation of IB. In addition, 9Z,11E-CLA attenuated TPA-induced phosphorylation of extracellular signal-regulated protein kinase, p38 mitogen-activated protein kinase and Akt. To further elucidate the molecular mechanism underlying the inactivation of NF-B by 9Z,11E-CLA, we investigated its effect on TPA-induced activation of IB kinase (IKK), an upstream kinase that regulates NF-B via phosphorylation and degradation of IB. 9Z,11E-CLA treatment down-regulated phosphorylation and catalytic activities of IKK/ß in TPA-treated mouse skin. Co-treatment of mouse skin with the IKKß-specific inhibitor SC-514 (1 µmol) attenuated TPA-induced activation of Akt and NF-B, and also the expression of COX-2 in hairless mouse skin. Taken together, 9Z,11E-CLA inhibits NF-B driven-COX-2 expression by blocking the IKK and PI3K-Akt signaling in TPA-treated hairless mouse skin in vivo, which may account for its previously reported anti-tumor promoting effects.


Abbreviations: CLA, Conjugated linoleic acid; COX-2, cyclooxygenase-2; TPA, 12-O-tetradecanoylphorbol-13-acetate; NF-B, nuclear factor-kappaB; ERK, extracellular signal-regulated protein kinase; IKK, IB kinase

Lani,
Thanks for this interesting post.
Do you know which source of CLA was used in the experiments?
Does it also mean that CLA could be bioavailable through the skin instead of by mouth?

answers for Heblaj
 

9Z,11E-CLA was purchased from Cayman Chemical Co. of Ann Arbor, MI
treatment consisted of applying 9Z,11 E-CLA and TPA (Alexis Biochemicals of San Diego) which had been dissolved in 200 microliters of acetone topically to the dorsal skin area

all mice were hairless and MALE! and were housed with 12 hrs of light and 12 hrs of dark

Based on the following Safety Data Sheet this 9Z,11E-CLA fatty acid looks more like a poor man's whiskey (90% ethyl alcohol)! http://www.caymanchem.com/msdss/90140m.pdf

How would this be administered to humans if systemic doses were required?

well Heblaj
 

one of the authors' email address is listed above. He seems to come from a School of Pharmacy. Perhaps a polite email asking him to speculate????