Protective effect of cepharanthin on cisplatin-induced renal toxicity through metallothionein expression
Introduction
Cancer chemotherapy contributes to the improvement of not only disease states but also quality of life for patients. However, it frequently has adverse effects, making it difficult to achieve a complete cure, and sometimes being a dose-limiting factor for its use. Cisplatin (cisplatinum or cis-diamminedichloroplatinum (II), CDDP) is a highly effective anti-cancer agent, which was accidentally discovered in the 1960's (Rosenberg et al., 1969). While it has severe adverse effects including ototoxicity, neurotoxicity, myelosuppression, allergic reactions and emetogenicity (Wang and Lippard, 2005), the main side effect of CDDP as a dose-limiting factor is nephrotoxicity (Arany and Safirstein, 2003, dos Santos et al., 2012). Therefore, management of these problems, especially renal toxicity, is important for cancer therapy with CDDP. Although potent antagonists of the serotonin 5-HT3 receptor and NK1 receptor were introduced recently, resulting in a reduction of CDDP-induced vomiting (Navari, 2003), renal toxicity remains a major problem in CDDP treatment (dos Santos et al., 2012).
Metallothionein (MT) is a cysteine-rich, low molecular-weight protein with high affinity for metals, such as cadmium (Cd), mercury (Hg), bismuth (Bi) and zinc (Zn) (Vasak and Meloni, 2011). MT is thus considered to have a protective role against heavy metal-induced toxicity and other related disorders (Coyle et al., 2002, Namdarghanbari et al., 2011). MT is produced in various organs, including the liver and kidney, in response to various heavy metals. Therefore, it was suggested that MT production in the kidney contributed to the reduction in CDDP-induced renal toxicity. Regarding this, there is a line of evidence demonstrating that treatment with MT inducers including bismuth reduced the renal toxicity of CDDP (Naganuma et al., 1985, Naganuma et al., 1987, Satoh et al., 1997, Petering et al., 2006).
MT production is induced not only by heavy metals but also by medicines, physical stress and chemical mediators such as cytokines (Coyle et al., 2002). It was also reported that some herbal medicines induced MT expression in the liver and small intestine (Anjiki et al., 2005) and in the kidney (Shibayama et al., 2007). Cepharanthin® (CE), a biscoclaurin alkaloid prepared from extracts of Stephania cepharantha HAYATA, has four active agents; cepharantine, isotetrandrine, berbamine and cycleanine. It has been widely used in Japan for more than 40 years to treat a variety of acute and chronic diseases (Furusawa and Wu, 2007, Rogosnitzky and Danks, 2011). Since CE has an anti-cancer effect and acts as an antioxidant, we speculated that it induces production of MT in the kidney, thereby reducing CDDP-induced renal toxicity.
We initially found that CE did induce the expression of MT mRNA in cultured cells derived from kidney and of the MT protein in mouse kidney. Based on these findings, we further investigated the protective effects of CE on the renal toxicity of CDDP.
Section snippets
Cell culture
COS-7 (RCB0539) and MDCK (RCB0995) cells were obtained from RIKEN BioResource Center (Tsukuba, Japan). Both cell lines were maintained in high-glucose Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum, 100 units/ml penicillin-G, 100 μg/ml streptomycin and 2.5 μg/ml fungizone at 37 °C under 5% CO2/95% air.
Animal experiments
All animal experiments were performed according to the guidelines for the care and use of laboratory animals approved by Okayama University and the Japanese
Expression of MT mRNA induced by CE in COS-7 and MDCK cells
There are four isoforms of MT, MT-I, -II, -III and -IV, in mammals. The MT-I and -II genes are expressed in many tissues including brain, liver and kidney tissues, while MT-III and MT-IV are expressed mainly in the central nervous system and squamous epithelia (Coyle et al., 2002). Therefore, we investigated the expression of MT-I/II mRNA, considered the main isoforms in kidney, in cells derived from the kidney after the administration of CE.
MT mRNA was detected 3 h after the administration of
Discussion
Renal toxicity is the most common adverse effect of CDDP, thereby affecting chemotherapy using CDDP as a dose-limiting factor. Since it has been suggested that free radicals are related to the renal toxicity of CDDP, antioxidants such as vitamin C, vitamin E and glutathione, contribute to a reduction in CDDP-induced renal toxicity (dos Santos et al., 2012). At present, CDDP is often administered with a large amount of saline to prevent renal toxicity (Launay-Vacher et al., 2008). However,
Conclusion
The present study demonstrated that pre-administration of CE reduced CDDP-induced renal toxicity, and the biosynthesis of MT partly contributes to the protective mechanisms against CDDP. As CE has anti-cancer and antioxidant properties, it is expected to better prevent CDDP-induced renal toxicity than other chemicals. In addition, CE should be easier to apply to chemotherapy against cancer than other chemicals, because CE has already been used in cancer therapy.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This study was supported in part by a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Science, Sports and Technology (NS).
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