A novel combination of Chinese medicines to treat advanced cancers and lymphomas tested in rats

Background Chinese medicine often targets more than one system and as such comprises several compounds, often in non-purified form, with treatments therefore consisting of whole extracts of herbs rather than isolated compounds. The additive and synergistic effects of the phytochemicals in OMN54, a novel mixture of extracts from three commonly used Chinese medicine components; Ganoderma lucidum, Salvia miltiorrhiza and Scutellaria barbata, were previously demonstrated to have potent anticancer activity. This study aims to test whether this heterogeneous, multifunctional and multitargeted agent has an acceptable toxicity profile. Methods We conducted preliminary and formal preclinical tolerability determination of OMN54 in SpragueDawley rats. In the preliminary study rats were given OMN54 by oral feeding daily for 14 days at doses of 1000mg/kg, 1750mg/kg, 2500mg/kg or 3000mg/kg per day. A subsequent daily dosing (x 28, 60, 120 or 180) formal toxicology study was conducted in male and female Sprague-Dawley rats at a dose of single dose of 2000mg/kg/day. Results Significant body weight loss was noted in one of the rats treated at 3000mg/kg/day, with decline beginning study day 11. This animal experienced mild GI toxicity in the form of diarrhoea. Gross observation indicated kidney damage (pale kidneys) in both this group and in one rat treated at 2500mg/kg/day. For the later studies, no body weight loss was noted over the course of the study. Blood counts and chemistry were not substantially altered following administration of OMN54, nor were there any findings on histological assessment of organs. Conclusion OMN54 was found to be well tolerated in rat models. OMN54 did not cause any microscopic, anatomic or pathologic changes in exposed animals at the concentrations and under the conditions employed in this study. Background Comparative studies in cancer research have recently demonstrated some uses of Chinese medicine in the West. This is particularly true in the field of cancer research [1-4]. The present study investigates OMN54, a proprietary multifunctional and multitargeted oral formulation of extracts manufactured from the following three commonly used Chinese medicinal plants, namely Ganoderma lucidum (Lingzhi), Salvia miltiorrhiza (Danshen) and Scutellaria barbata (Banzhilian), for its effectiveness and toxicity. OMN54 is a complex mixture of phytochemicals, the additive and synergistic effects of which are likely responsible for the potent anti-cancer activity noted. Cultivated in China, Japan and Korea, Ganoderma lucidum is considered a ‘superior herb’ according to Shennong Bencao Jing (Shen Nung Pen Ts’ao Ching), a Chinese medicine classic dated AD 25. The cap and stem of the dried fruit body (sporophore) of Ganoderma lucidum are used in the commercial preparation of OMN54. Ganoderma lucidum inhibits nuclear factor kappa B (NFκB) and Activator Protein 1 (AP-1), thereby inhibiting the expression of urokinase-type plasminogen activator (uPA) and its receptor uPAR [5]. Ganoderma lucidum inhibits colorectal [6] and breast cancer [7] cells through down regulating oestrogen receptor and NF-κB signalling. Ganoderma lucidum also suppresses cell adhesion and cell migration of highly invasive breast [8, 9] and prostate cancer [8] cells. Recent research elucidated a role for specific long chain fatty acids (nonadecanoic acid (C19:0), heptadecanoic acid(C17:0), octa-(C18:0) and hexadecanoic acids (C16:0) from the spores of Ganoderma lucidum to the observed anti-cancer activity [10] by means of in vitro HL-60 cell growth inhibition assays in addition to the previously identified polysaccharides and triterpenes components [11]. These data suggest that Ganoderma lucidum is a potential therapeutic dietary supplement to treat breast and prostate cancer. Extracts of Salvia miltiorrhiza, the second component of OMN54, are used in Chinese medicine to treat liver diseases [12]. Recent studies indicated that Salvia miltiorrhiza had anti-tumour potential and prevented Aflatoxin B1 (AFB1)-induced liver cell injury [13], suggesting that Salvia miltiorrhiza may prevent AFB1-induced hepatocarcinogenesis as evidenced by a decrease in AFB1-DNA adduct formation as well as AFB-1 induced oxidative DNA damage (8 hydroxydeoxyguanosine) in rat liver [13] following administration. Finally, Salvia miltiorrhiza treatment results in apoptosis in a number of cancer cell lines, such as hepatoma [14] and leukemia [15, 16] as evidenced by cytoplasmic and nuclear shrinkage, chromatin condensation and membrane blebbing, all characteristic morphological alterations of apoptosis as well as time and dose dependent increase of apoptotic sub-G1 cells. The stems and leaves of Scutellaria barbata are the third component of OMN54. Research showed that Scutellaria barbata had anticancer activity such as apoptosis induction in lung cancer [17], hepatocellular carcinoma [18], ovarian cancer [19] and colon cancer cells [20] through down regulation of Bcl-2 [21]. Recent research identified a number of diterpenoid alkaloids that may contribute to this cytotoxic activity of Scutellaria barbata [22, 23]. The present study aims to investigate in vivo safety of OMN54 and focuses on the formal repeat dose toxicology in Sprague Dawley rats conducted in preparation for Phase I clinical study.