Total Flavonoids of Litsea Coreana Enhance the Cytotoxicity of Oxaliplatin by Increasing Gap Junction Intercellular Communication

Abstract

Oxaliplatin is widely used in the treatment of variety of cancers, including cancer of the testis and colorectum. Gap junctions (GJs) can amplify the cytotoxicity of antinoeoplastic drugs through the bystander effect in different cancer cells. In this study, we demonstrate that total flavonoids of litsea coreana (TFLC), one extract from the dried leaves of litsea coreana leve, increase the cytotoxicity of oxaliplatin in mouse testicular cancer I-10 cells. We found that cell survival was substantially decreased only when functional GJs formed in I-10 cells. TFLC increased oxaliplatin cytotoxity (inducing cell death and apoptosis) by enhancing gap junction intercellular communication (GJIC) through elevated Cx43 protein expression. Furthermore, apoptosis-related protein (Bax, Bcl-2, caspase-3/9) results showed that the Bax/Bcl-2 ratio and activated caspase-3/9 increased when TFLC was used compared with treatment with oxaliplatin alone, which suggests that the mechanism of increased oxaliplatin-induced apoptosis was through the mitochondrial pathway. These results demonstrate that TFLC can enhance the cytotoxicity of oxaliplatin, and that these processes may be regulated in testicular tumor cells through GJ-mediated regulation of tumor cell apoptosis.Key words litsea coreana; gap junction; apoptosis; oxaliplatin Gap junctions (GJs) are intercellular channels that connect the cytoplasm of adjacent cells. They have vital implication in regulation of homeostasis, morphogenesis, cell differentiation, and growth control in multicellular organisms. GJs are consisted with core protein-connexin. A considerable number of studies have established that GJs are decreased in variety of tumors.1-4) Furthermore, enhancement of GJs increases cytotoxicity during cancer chemotherapy and radiotherapy. 5,6) It is well known that dietary intake of fruit or herbal health drinks containing sufficient flavanoids will reduce the occurrence risk of cancer (e.g. breast, lung and colon). Total flavonoids of litsea coreana (TFLC), one of the flavonoids, is the key pharmacologically active constituents extracted from litsea coreana leve which is a traditional Chinese medicine. TFLC primarily consists of five flavonoids, identified as quercetin-3-β-D-galactoside, quercetin-3-β-D-glucoside, kaempferol-3-β-D-glucoside, kaempferol-3-β-D-galactoside and catechin. Oxaliplatin (OHP) [1,2-diaminocyclohexane (trans-1) oxolatoplatinum(II)], a related platinum based chemotherapeutic agent, reacting with GC-rich areas of DNA, forming both intrastrand and interstrand cross-links, leading to G2 arrest and to apoptosis or necrosis.10) It is commonly used in the treatement of testicular cancer. Wang et al. also demonstrated that the cytotoxicity of oxaliplatin was increased in the presence of GJ and increasing GJ function enhanced cytotoxicity of oxaliplatin in the cells with functional GJ.11) And a simple inference from these reports is that induction of apoptotic or necrotic processes in one cell can cause a molecular "death signal" to be transmitted to neig...

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