Zyflamend Mediates Therapeutic Induction of Autophagy to Apoptosis in Melanoma Cells

Abstract

Melanoma is the most aggressive form of skin cancer. The rising incidence of melanoma and its poor prognosis in advanced stages are compelling reasons to identify novel therapeutic agents. Though isolated dietary components such as lycopene, resveratrol, and isothiocyanate compounds have been shown to provide limited protection against cancer development, the use of whole herbs and herbal extracts for the treatment of cancer remains of great interest. As suggested by earlier studies, the antiinflammatory activity of many plants available as intact products or as extracts has long been considered for supplemental therapeutics for cancer. Zyflamend, a unique multiherbal extract preparation, is a promising antiinflammatory agent that has also been suggested to regulate multiple pathways in cancer progression. As Zyflamend contains ingredients that can suppress tumor cell proliferation, invasion, angiogenesis, and metastasis through regulation of inflammatory pathway products, we hypothesized that this preparation might inhibit melanoma proliferation. To test this hypothesis, we studied the effect of Zyflamend on melanoma proliferation. Here, we present that Zyflamend inhibits melanoma growth by regulating the autophagy-apoptosis switch. Based on the responsible molecular mechanisms of Zyflamend, our study highlights the importance of the use of herbal preparations for the prevention and treatment of cancer.

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

“…Our data pertaining to Zyflamend and several studies from other laboratories (Bemis et al, 2005;Burke et al, 2015;Capodice et al, 2009;Ekmekcioglu et al, 2011;Huang, Chen, et al, 2011;Huang et al, 2014;Kim et al, 2012;Kunnumakkara et al, 2012;Mohebati et al, 2012;Rafailov et al, 2007;Sandur et al, 2007;Yan et al, 2012;Yang et al, 2007Yang et al, , 2008 reveal diverse mechanisms of action, possibly explaining its robust effects using in vivo models of tumorigenesis at oral doses that mimic human intakes (Huang, Chen, et al, 2011;Kunnumakkara et al, 2012). Because herbal extracts are composed of multiple compounds, it is difficult to directly extrapolate a standard concentration.…”

“…Its original formulation almost 2 decades ago was based on those herbs that had antioxidant and antiinflammatory properties. Its subsequent use in experimental investigations in an assortment of cancer models has drawn attention by a variety of laboratories interested in the role of natural products in health and disease (Bemis et al, 2005;Burke et al, 2015;Capodice et al, 2009;Ekmekcioglu et al, 2011;Huang, Chen, et al, 2011;Huang et al, 2014;Kim et al, 2012;Kunnumakkara et al, 2012;Mohebati et al, 2012;Rafailov et al, 2007;Sandur et al, 2007;Yan et al, 2012;Yang et al, 2007Yang et al, , 2008. There are always concerns regarding reproducibility and quality control of commercial products.…”

“…To date, there have been 14 research articles investigating the anti-cancer effects of this blend, covering in vitro, preclinical and clinical studies involving the prostate, bone, skin, kidney, breast and pancreas (Bemis, Capodice, Anastasiadis, Katz, & Buttyan, 2005;Burke et al, 2015;Capodice et al, 2009;Ekmekcioglu et al, 2011;Huang, Chen, et al, 2011;Huang et al, 2014;Kim et al, 2012;Kunnumakkara et al, 2012;Mohebati et al, 2012;Rafailov, Cammack, Stone, & Katz, 2007;Sandur et al, 2007;Yan, Xie, Capodice, & Katz, 2012;Yang et al, 2007Yang et al, , 2008, with prostate being the predominant focus. It has been reported that a number of its constituents act synergistically such that physiological doses are possible (Zhao, Collier, Huang, & Whelan, 2014) and multiple mechanisms of action have been linked in a variety of cancer cell lines by down regulating the androgen receptor (Huang, Chen, et al, 2011;Huang et al, 2014;Yan et al, 2012), insulin-like growth factor-1R (Huang, Chen, et al, 2011;, class I and II HDACs (Huang, Chen, et al, 2011;Huang et al, 2014), COX-1 and COX-2 activities (Bemis et al, 2005;Ekmekcioglu et al, 2011;Kunnumakkara et al, 2012), 12-LOX and Rb protein phosphorylation (Yang et al, 2007), and the up regulation of tumour suppressor genes such as p21 and p27 (Bemis et al, 2005;Huang et al, 2014). Zyflamend has also been shown to modulate NF-κB activation (Burke et al, 2015;Kunnumakkara et al, 2012;Sandur et al, 2007), iNOS (Ekmekcioglu et al, 2011), apoptotic pathways (Ekmekcioglu et al, 2011;…”

“…It has been reported that a number of its constituents act synergistically such that physiological doses are possible (Zhao, Collier, Huang, & Whelan, 2014) and multiple mechanisms of action have been linked in a variety of cancer cell lines by down regulating the androgen receptor (Huang, Chen, et al, 2011;Huang et al, 2014;Yan et al, 2012), insulin-like growth factor-1R (Huang, Chen, et al, 2011;, class I and II HDACs (Huang, Chen, et al, 2011;Huang et al, 2014), COX-1 and COX-2 activities (Bemis et al, 2005;Ekmekcioglu et al, 2011;Kunnumakkara et al, 2012), 12-LOX and Rb protein phosphorylation (Yang et al, 2007), and the up regulation of tumour suppressor genes such as p21 and p27 (Bemis et al, 2005;Huang et al, 2014). Zyflamend has also been shown to modulate NF-κB activation (Burke et al, 2015;Kunnumakkara et al, 2012;Sandur et al, 2007), iNOS (Ekmekcioglu et al, 2011), apoptotic pathways (Ekmekcioglu et al, 2011;Kim et al, 2012;Kunnumakkara et al, 2012), and aryl hydrocarbon receptor expression (Mohebati et al, 2012). It is believed that it is the combination of bioactives that accounts for modulation of multiple pathways at relatively low doses (as described in Huang, Chen, et al, 2011;Zhao et al, 2014).…”

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

“…Zyflamend (New Chapter, Inc. Brattleboro, VT) is a poly-herbal supplement derived from the extracts of ten different herbs: rosemary, turmeric, holy basil, ginger, green tea, hu zhang, barberry, oregano, Chinese goldthread, and baikal skullcap. Most research using Zyflamend has focused its effects on a variety of cancer models, including oral [ 11 ], mammary [ 12 ], bone [ 13 ], pancreas [ 14 , 15 ], skin [ 11 , 16 ], colorectal [ 15 ], with an emphasis on prostate [ 6 – 9 , 17 – 21 ], and its beneficial effects appear to be related to the synergy of action of its components [ 22 ]. The effects of Zyflamend and its mechanisms on prostate cancer has been reviewed elsewhere and can be summarized in Fig.…”