The Biomedical Outlook: Focus on Cancer Series (1)

How can Chinese Herbal Medicine Improve the Therapeutic Window for Colorectal Cancer Patients Receiving Chemotherapy?

Introduction

The roots of Chinese Herbal Medicine (CHM) are obscure; although the practice is believed to have originated around the 3^rd Century B.C. Modern CHM practiced in Western countries encompasses traditions not only from China, but from other South East Asian countries such as Japan and Vietnam. The basis of many diseases, including cancer, is believed to arise from disharmony between the interdependent forces of ‘Yin’ and ‘Yang’, thereby leading to disruption of ‘Qi’, or life force. The premise of CHM therefore is to redress the balance of Yin and Yang to restore health[1]. In a study exploring attitudes of clinical oncologists in Japan (which has adopted western medical practice) to CHM, Hyodo revealed that the majority had a poor understanding of its applicability and raised concerns relating to a lack of evidence and safety[2]. However, a search for the terms ‘chinese herbal medicine’ + ‘cancer’ in MEDLINE reveals a gradual increase in the published literature, with 22 results from 1992 to 241 in 2012. In particular, interest is growing around using CHM as an adjunct to chemotherapy (CT) to reduce the burden of toxicity associated with certain regimens. This article examines the potential of three CHM compounds in reducing CT toxicity in patients with colorectal cancer (CRC), which remains the second leading cause of cancer-related death worldwide[3].

Tanshinone IIA (TIIA)

Tanshinone is a compound extracted from the roots of Chinese red sage (Salvia miltiorrhiz), the pharmacology of which has been extensively studied. Su and colleagues first showed TIIA to have potent anti-proliferative and pro-apoptotic activity in colon adenocarcinoma cell lines which was in part dependent on P53 and P21 upregulation[4]. These findings were later extended to a mouse xenograft model implanted with Colo205 in which the antineoplastic action of the CT agent 5-FU were potentiated four-fold with the addition of TIIA[5]. This may be related to reduce expression of LC3-II, a marker of autophagy. Inhibition of autophagy has recently been shown to sensitise CRC cells to oxaliplatin, a key component of the FOLFOX-4 (5-FU, oxaliplatin and leucovorin) regimen which is frequently used as adjuvant CT for stage III and IV CRC, and is associated with nausea, vomiting, diarrhea and sensory neuropathy at moderate doses[6, 7]. Thus, TIIA may overcome resistance to CT frequently used for CRC therapy, thereby enabling administration of reduced doses to limit toxicity.

New work suggests TIIA may be able to modulate epigenetic components to impact on gene expression in vivo. Tu et al. show TIIA to inhibit micro-RNA (mir) 155a in macrophages, thereby leading to decreased expression of pro-inflammatory cytokines[8]. Chronic levels of inflammation, which often correlate with COX-2 overexpression, have been shown to enhance the expression of dihydropyrimidine dehydrogenase (DPD), an enzyme which eliminates 5-FU in CRC cell lines[9]. Therefore, future research should examine whether TIIA in addition to COX-2 inhibitors (e.g. celecoxib) and DPD inhibitors (e.g. CDHP) could potentiate an anti-inflammatory effect to minimize doses of CT required. Other work from hepatocellular carcinoma cell lines indicates that TIIA sensitizes cells to the redox-cycling agents. This may be explained by the stabilizing effects of TIIA on mitochondria [10] and it is therefore feasible that TIIA enhances ROS production and ultimately apoptosis independent of P53, which is mutated in the majority of CRC cases. The mechanisms by which TIIA exerts its anti-cancer effects requires further elucidation. While studies reveal danshen ( a source of TIIA) has a favourable safety profile in small samples of stroke patients [11], further work is needed to identify any potential side-effects arising from multi-drug interactions.

PHY906

PHY906 is a concoction of four separate Chinese herbs, namely Scutellaria baicalensis Georgi , Glycyrrhiza uralensis Fisc, Paeonia lactiflora Pall, Ziziphus jujuba Mill, which has been used for almost 2000 years as an antidiarrheal agent, antiemetic and appetite stimulator[12]. Evidence both in mice and from human clinical trials has emerged suggesting PHY906 may reduce the toxicity associated with irinotecan (CPT-11), which is frequently used for CRC as part of the FOLFIRI regimen[13]. Similar to the campothecins from which it is derived, the major dose limiting side-effect of irinotecan is grade3/4 diarrhea and dehydration. Colorectal tumour-bearing mice given high dose intraperitoneal irinotecan together with PHY906 showed a reduction in weight loss compared to mice receiving irinotecan alone [14]. The mechanism underlying the effects of PHY906 have only been partially elucidated, with evidence from mice showing anti-inflammatory effects, thereby limiting intestinal damage initiated by the irinotecan metabolite SN38[15, 16].Other studies further show that PHY906 does not affect the pharmacokinetics of 5-FU and irinotecan, which is reflected by the fact that no published studies show any adverse effects arising from PHY906 use[14]. A phase I placebo-controlled randomized clinical trial on a small population of advanced CRC patients showed good safety and tolerability of PHY906 with 5-FU and leucovorin, reductions in diarrhea and vomiting and subjective reports by patients and relatives of improvements in quality of life[14]. Although this study provides evidence of PHY906 safety in humans, larger samples are required to substantiate the anti-tumour effects when it is combined with chemotherapy. PHY906 is currently being evaluated alongside other chemotherapeutics in clinical trials for unresectable Hepatocellular Carcinoma (HCC) (NCT01666756) and pancreatic cancer (NCT00411762), data from which will be invaluable for gauging PHY906 in vivo safety for CRC also.

Ginseng

As the root of the plant Panax notoginseng, ginseng was included in the earliest known Chinese pharmacopoeia dating back over 2000 years[17] . Research on ginseng in CRC has mostly focused on its chemopreventive role, although it has been found to possess anti-tumour activities. Cheng et al. have shown that the HG-rich pectin ginseng fractions induce cell cycle arrest in HT-29 cell lines, which may depend on activation of P53 and P21 [18, 19]. The active compound 20S-Rg3 has been found to display similar properties in these cells[20], while another active component Rh2 may both induce apoptosis and potentiate the activities of natural anti-oxidants[21]. The RG3 compound has also been found to inhibit NF-kB activation and wnt/β-catenin signaling[22], thereby simultaneously impeding cell proliferation and inflammation. This suggests a possible synergy between ginseng and TIIA in enhancing the effects of 5-FU mentioned above. Indeed, ginseng has been found to combine well with other tumoricidal natural compounds such as epigallotechin[23]. In addition, the Rg3 and Rb2 compounds have demonstrated anti-angiogenic activity both in vitro and in vivo [24, 25]. Conceivably, ginseng combined with bevacizumab, an anti-VEGF antibody which is FDA approved for metastatic CRC patients, could reduce the doses of bevacizumab required and overcome dose-limiting toxicities including GI perforation and thromboembolic complications [26, 27]. The risk of the latter complication may be decreased through the anti-coagulant properties of the Rg2 ginsenoside[28].

The major ginseng varieties examined in the literature are white (WG) and red varieties (RG). In comparing the synergistic activity of these two varieties with 5-FU in vitro Fishbein and colleagues showed RG to be more potent than WG in suppressing proliferation of HCT-116 cells[29]. These results were confirmed in a separate study[30]. Perhaps research using WG, RG and 5-FU together should be performed to assess whether bioactive components of these separate varieties complement each other.Du and colleagues found that panaxadiol, a ginseng saponin, combined with irinotecan displayed enhanced apoptosis compared to irinotecan alone[31]. Similar findings have since emerged for combination of panaxadiol with 5-FU [32]. However, one of the well-defined properties of ginseng is the stimulation of GI peristalsis[33], leading to potential exacerbation of irinotecan-associated diarrhea. This highlights the need for more in vivo data to model the safety of combining ginseng and CT. One notable study evaluating ginseng safety in humans is that by Yun et al. examining its potential as a cancer chemopreventive. No adverse effects were reported[34]. A randomized placebo-controlled clinical trial evaluating the safety of Korean Ginseng in alleviating symptoms of fatigue in CRC patients receiving FOLFOX-6 therapy has recently commenced (NCT02039635) which will provide more information. Importantly, ginseng has been shown to alleviate symptoms of depression and anxiety in a number of animal models [35]. Studies show improved psychological wellbeing to increase the tolerance of patients to dose-limiting CT toxicity[36]. Thus, ginseng and other herbal remedies may indirectly improve the therapeutic window. Collaboration between the fields of molecular oncology and neuroscience will undoubtedly contribute to characterizing the properties of ginseng as a CT adjunct.

Conclusions

CHM has previously been dismissed by mainstream western medicine due to its association with folklore and the supernatural. However, research into this area has witnessed a revival, especially in CHM as adjuncts to reduce dose-limiting toxicities of CT. The three compounds above all display potent anti-tumour activity in vitro but work is necessary to clarify their tolerability alongside CT in living organisms. The plethora of clinical trials currently underway for PHY906 and ginseng will be informative in this respect. Future work may also focus on identifying metabolic pathways for CHMs and biomarkers predicting response.