Zyflamend, a polyherbal mixture, inhibits lipogenesis and mTORC1 signalling via activation of AMPK

Zhao, Yi; Donohoe, Dallas R.; Huang, E‐Chu; Whelan, Jay

doi:10.1016/j.jff.2015.06.051

Cited by 8 publications

(11 citation statements)

References 43 publications

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“…Similar results were replicated in a variety of immortalized prostate-derived cells lines [ 8 ] and in the HCT116 colorectal cell line (Additional file 2 : Figure S2). Because Zyflamend has been shown to change the energetics of CWR22Rv1 cells [ 3 , 10 ], levels of ATP were determined. In the presence of Zyflamend, ATP levels were reduced by ~ 40% (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Zyflamend is a unique blend of ten herbal extracts with tumor suppressor properties whose biochemical and physiological effects have been replicated in different laboratories, at different times, using different lots, with similar doses/concentrations [ 6 – 8 , 10 , 11 , 13 – 17 , 19 , 21 , 43 ]. The quality control of this preparation has been summarized elsewhere [ 7 ] and is most likely responsible for the reproducibility of results.…”

Section: Discussionmentioning

confidence: 99%

“…The quality control of this preparation has been summarized elsewhere [ 7 ] and is most likely responsible for the reproducibility of results. Importantly, the effects of Zyflamend have been reported in a variety of cell lines, not just prostate cancer cells (CWR22, CWR22R, CWR22Rv1, PC3, LNCaP, RWPE-1, RAW 264.7, H1299, KBM-5, U266, MeW0, A365, MSK-Leuk1, HaCaT, HCT116, THP-1, HEK293) [ 6 – 8 , 10 – 19 , 21 , 43 ]. While there is clinical evidence for the beneficial effects of Zyflamend on prostate cancer [ 9 , 18 , 20 , 44 ], it is not possible to tease out the contributions and/or interactions of each constituent due to the high number of possible combinations (as many as 1024).…”

Section: Discussionmentioning

confidence: 99%

“…Relapse in the absence of androgens (castrate-resistant prostate cancer) is inevitable for most individuals and is associated with increased expression and activation of the androgen receptor, a major determinant in survival [ 4 , 5 ]. Due to the poor prognosis of castrate-resistant prostate cancer, concomitant use of natural products to enhance effectiveness is being explored clinically and experimentally [ 3 , 6 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Clinically, treatment with Zyflamend and/or metformin (activator of AMPK) had benefits in castrate-resistant prostate cancer patients who no longer responded to a variety of treatments (e.g., hormone ablation, immune-, chemo-, and radiation therapy). Recently, it was determined that tumor suppressor properties of Zyflamend are associated with the activation of AMPK and its downstream signaling, where siRNA knockdown, pharmacological inhibition and over expression of AMPK confirmed Zyflamend’s involvement [ 10 ]. This involves inhibiting the mammalian target of rapamycin complex-1 (mTORC1) and protein synthesis, lipogenesis by targeting the expression of (i) fatty acid synthase, (ii) the sterol regulatory element-binding transcription factor-1c, and (iii) inhibiting the activity of acetyl CoA carboxylase (ACC).…”

Section: Introductionmentioning

confidence: 99%

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Concurrent regulation of LKB1 and CaMKK2 in the activation of AMPK in castrate-resistant prostate cancer by a well-defined polyherbal mixture with anticancer properties

MacDonald

Bettaieb

Donohoe

et al. 2018

BMC Complement Altern Med

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BackgroundZyflamend, a blend of herbal extracts, effectively inhibits tumor growth using preclinical models of castrate-resistant prostate cancer mediated in part by 5′-adenosine monophosphate-activated protein kinase (AMPK), a master energy sensor of the cell. Clinically, treatment with Zyflamend and/or metformin (activators of AMPK) had benefits in castrate-resistant prostate cancer patients who no longer responded to treatment. Two predominant upstream kinases are known to activate AMPK: liver kinase B1 (LKB1), a tumor suppressor, and calcium-calmodulin kinase kinase-2 (CaMKK2), a tumor promotor over-expressed in many cancers. The objective was to interrogate how Zyflamend activates AMPK by determining the roles of LKB1 and CaMKK2.MethodsAMPK activation was determined in CWR22Rv1 cells treated with a variety of inhibitors of LKB1 and CaMKK2 in the presence and absence of Zyflamend, and in LKB1-null HeLa cells that constitutively express CaMKK2, following transfection with wild type LKB1 or catalytically-dead mutants. Upstream regulation by Zyflamend of LKB1 and CaMKK2 was investigated targeting protein kinase C-zeta (PKCζ) and death-associated protein kinase (DAPK), respectively.ResultsZyflamend’s activation of AMPK appears to be LKB1 dependent, while simultaneously inhibiting CaMKK2 activity. Zyflamend failed to rescue the activation of AMPK in the presence of pharmacological and molecular inhibitors of LKB1, an effect not observed in the presence of inhibitors of CaMKK2. Using LKB1-null and catalytically-dead LKB1-transfected HeLa cells that constitutively express CaMKK2, ionomycin (activator of CaMKK2) increased phosphorylation of AMPK, but Zyflamend only had an effect in cells transfected with wild type LKB1. Zyflamend appears to inhibit CaMKK2 by DAPK-mediated phosphorylation of CaMKK2 at Ser511, an effect prevented by a DAPK inhibitor. Alternatively, Zyflamend mediates LKB1 activation via increased phosphorylation of PKCζ, where it induced translocation of PKCζ and LKB1 to their respective active compartments in HeLa cells following treatment. Altering the catalytic activity of LKB1 did not alter this translocation.DiscussionZyflamend’s activation of AMPK is mediated by LKB1, possibly via PKCζ, but independent of CaMKK2 by a mechanism that appears to involve DAPK.ConclusionsTherefore, this is the first evidence that natural products simultaneously and antithetically regulate upstream kinases, known to be involved in cancer, via the activation of AMPK.Electronic supplementary materialThe online version of this article (10.1186/s12906-018-2255-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%