An oriental herbal cocktail, ka-mi-kae-kyuk-tang, exerts anti-cancer activities by targeting angiogenesis, apoptosis and metastasis

Rigorous and systematic pre-clinical studies are necessary and essential to establish the efficacy and safety of Oriental herbs and formulas in order to transform traditional herbal practices into evidence-based medicine. Here we evaluated the anti-cancer activities of the ethanol extract of Ka-mi-kae-kyuk-tang (KMKKT), a formula of ten Oriental herbs, with a battery of in vitro and in vivo mechanism-based biomarkers involving angiogenesis, apoptosis and metastasis. The results show that KMKKT suppressed the vascular endothelial responses by inhibiting basic fibroblast growth factor (bFGF)-induced ERK1/2 phosphorylation, cell migration as well as tube formation in the human umbilical vein endothelial cell model, and decreased the hypoxia-induced HIF1α and vascular epithelial growth factor (VEGF) expression in the mouse Lewis lung carcinoma (LLC) cells in vitro, and inhibited the bFGF-induced angiogenesis in chick chorioallantoic membrane model, and in the Matrigel plugs in mice. Intraperitoneal delivery of KMKKT potently inhibited the growth of the subcutaneously inoculated LLC cells in syngenic mice. In addition, KMKKT inhibited the invasion ability of the mouse colon 26-L5 cancer cells in vitro and decreased their formation of liver metastasis when intraportally inoculated in syngenic mice. Furthermore, KMKKT suppressed the growth of the human PC-3 prostate cancer xenografts in athymic nude mice and averted the cancer-related body weight loss. The in vivo cancer growth suppression was associated with a decreased microvessel density and VEGF abundance as well as an increased PARP cleavage and the TUNEL-positive apoptosis. Together, our data support broad-spectra in vivo anti-cancer activities of KMKKT targeting angiogenesis, apoptosis and metastasis without any adverse effect on the body weight. This formula merits serious consideration for further evaluation for the chemoprevention and treatment of cancers of multiple organ sites.
pin yin Name origin Gms %
dong gua zi Benincasa hispida (seed) China 30 17.24
ba ji Bletilla striata (root and tuber) China 15 8.62
la ya ban (shan ci gu) Tulipa edulis (stem tuber) Korea 15 8.62
ren shen Panax ginseng (root) Korea 15 8.62
chi dou Phaseolus angularis (seed) Korea 30 17.24
hu jiao mu Zanthoxylum piperitum (seed) Korea 12 6.9
bai hua bai jiang Patrinia villosa (root) China 15 8.62
huang qi Astragalus membranaceus (root) Korea 15 8.62
chao xian dang gui Angelica gigas Nakai (root) Korea 12 6.9
e jiao Asini gelatinum Korea 15 8.62

Introduction
Cancers of the lung, prostate and colorectal account for the majority of cancer mortality in the USA and in the Western countries (1). Chemotherapy using available cytotoxic anti-cancer drugs for advanced-stage malignancies in the lung and prostate offers little survival benefit (2,3). All current chemotherapy modalities have significant side effects and dose-limiting toxicities (2,3). It is now being increasingly recognised that intervening critical processes of cancer growth and development including angiogenesis and metastasis with naturally occurring herbal and phytochemical agents to achieve chemo-prevention is crucial to decreasing the morbidity and mortality of these and other cancers.

Chinese/Oriental herbal medicine has long been used for treating malignancies. Whereas single herbs are seldom used alone, herbal cocktails take advantage of synergy and interactions among a myriad of phytochemicals present in the different herbs to achieve therapeutic efficacy targeting multiple biological and pathological processes while minimising side effects. However, herbal remedies are yet to be integrated into main stream medicine due to a number of challenges, including herbal standardisation and quality control issues, safety and toxicity concerns, interactions with existing therapeutic modalities, a lack of proven efficacy by standard clinical trials and a lack of mechanistic details, to name a few (4). Rigorous in vitro and pre-clinical animal studies will be essential and necessary to evaluate their efficacy and safety before clinical trials can be contemplated for the chemoprevention and treatment of these major cancers in humans and to transform traditional herbal practices into ‘evidence-based medicine’.

Here we report the evaluation of an anti-cancer formula of ten Oriental herbs, Ka-mi-kae-kyuk-tang (KMKKT) (5), with a battery of in vitro and in vivo pre-clinical tests. In addition to tumour cell proliferation and apoptosis, we focused on angiogenesis assays because of the central importance of angiogenesis in supporting tumour growth and metastasis (6–9). Angiogenesis in embryonic development, reproduction and wound healing is tightly regulated by a balance between the angiogenic inhibitors and activators and in neoplasia, the delicate balance is tilted to favour increased angiogenesis (6–9). In terms of the angiogenic activators, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been well documented (10–12). Even though VEGF is a primary mediator of angiogenic responses, bFGF is more potent than VEGF for stimulating the vascular endothelial mitogenesis. Hence bFGF is the most often used angiogenic polypeptide for experimental studies (13) and we used it for our angiogenesis tests in the current work. Tumour growth and progression require angiogenesis because in its absence tumour growth is restricted to 1–2 mm in diameter due to the physical constraint set by simple diffusion of nutrients and oxygen (6–12). In addition, angiogenesis and vascularisation provide an important avenue for the extravasation of metastatic tumour cells to the circulation and for them to re-establish in the other organ sites. Consequently, the inhibition of neo-angiogenesis has been considered an attractive and rationale approach to cancer chemoprevention and therapy (14,15). Thus, in the present study, we focused on the anti-angiogenic effects of KMKKT for screening purposes. We tested the in vivo efficacy of this formula against three models of mouse and human solid tumour growth or metastasis. The results support the merit of this cocktail for the chemoprevention and therapy of cancers of multiple organ sites.
Source:
Lee H-J, Lee E-O, Rhee Y-H, et al. Carcinogenesis (2006) 27 (12): 2455-2463. doi: 10.1093/carcin/bgl104

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