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Bufadienolides bufalin and cinobufagin are cardiotonic steroids isolated from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor. They have been shown to induce a wide spectrum of cancer cell apoptosis. However, the detailed molecular mechanisms of inducing apoptosis in hepatocellular carcinoma (HCC) are still unclear. In the present study, the apoptosis-inducing effect of bufalin and cinobufagin on HCC cell line HepG 2 was investigated. We found bufalin and cinobufagin induced marked changes in apoptotic morphology and significantly increased the proportion of apoptotic cells. This apoptotic induction was associated with an increase in Fas, Bax and Bid expression, a decrease in Bcl-2 expression, disruption of the mitochondrial membrane potential, release of cytochrome c, activation of caspase-3, -8, -9 and -10, and the cleavage of poly(ADP-ribose)polymerase (PARP), which indicated that bufalin and cinobufagin induced apoptosis through both Fas-and mitochondria-mediated pathways. In addition, caspase activation during bufalin-and cinobufagin-induced apoptosis was further confirmed by caspase-3 inhibitor Z-DEVD-FMK, caspase-8 inhibitor Z-IETD-FMK, caspase-9 inhibitor Z-LEHD-FMK and caspase-10 inhibitor Z-AEVD-FMK. The results showed that bufalin-and cinobufagin-induced apoptosis was blocked by these inhibitors and particularly by caspase-10 inhibitor. Taken together, bufalin and cinobufagin induce apoptosis of HepG 2 cells via both Fas-and mitochondria-mediated pathways, and a Fasmediated caspase-10-dependent pathway might play a crucial role. (Cancer Sci 2011; 102: 951-958) H epatocellular carcinoma (HCC) is one of the most common malignancies worldwide with 600 000 deaths per year, and its incidence is still on the rise.(1) Surgical treatments, such as liver resection and transplantation, are the first-line therapeutic strategies for HCC. However, the postoperative survival rate is only 30-40% at 5 years and recurrence is quite common in patients who have had a resection.(2) In addition, because HCC is a relatively chemo-resistant tumor and highly refractory to cytotoxic chemotherapy, systemic cytotoxic chemotherapy agents are minimally effective at improving the survival of patients with advanced HCC.(3,4) Therefore, development of novel chemotherapeutic agents and more effective therapies for the treatment of HCC are urgently needed. Recently, traditional Chinese medicines and their active components have attracted a great deal of attention as candidates for HCC therapy.(5)

The prevalence of hepatocellular carcinoma (HCC) worldwide parallels that of persistent infection with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV). According to recommendations by the World Health Organization guidelines for HBV/HCV, alpha-fetoprotein (AFP) testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients. These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades. In recent years, however, the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010, the European Association for the Study of the Liver in 2012, and the National Comprehensive Cancer Network in 2014. Other biomarkers, including the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxyprothrombin, Dickkopf-1, midkine, and microRNA, are being studied in this regard. Furthermore, increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors. Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment. However, further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.

Des‐γ‐carboxyprothrombin (DCP) is known as a tumour marker for hepatocellular carcinoma (HCC). Various tumour markers have been developed for serological diagnosis of cancers, including HCC, in order to increase the survival rate of cancer patients. The currently recommended combined testing of DCP and α‐fetoprotein (AFP) or Lens culinaris agglutinin‐reactive fraction of α‐fetoprotein has been established to diagnose HCC. This combined testing using several tumour markers helps to increase the sensitivity of diagnosis of HCC, thus significantly increasing the clinical usefulness of DCP. The excessive production of DCP may be related to worse tumour behaviour, such as the presence of vascular invasion and intrahepatic metastasis of HCC cells. A high level of DCP was suggested to be useful as one of the factors in new recipient selection criteria of liver transplantation. The clinical use of DCP, therefore, might play a vital role in predicting tumour behaviour in patients with HCC. That said, the basic mechanism of DCP production has not been fully clarified. Various factors such as vitamin K2 and γ‐glutamyl carboxylase may contribute to the production of DCP and have a complex relationship. Moreover, recent studies have revealed that DCP functions as a growth factor and might play significant roles in cancer progression. Thus, DCP represents a potential target of drug discovery to establish new chemotherapeutic strategy for HCC. However, various issues have to be resolved to construct a novel therapy for HCC‐targeting DCP. Innovation is required to make further progress in examining DCP.

In the past 10 years, many guidelines for hepatocellular carcinoma (HCC) have been published worldwide. To promote standard care for HCC, we systematically evaluated 17 current guidelines for HCC around the world, including 5 guidelines from the USA, 7 from Asia and 5 from Europe, according to the selection criteria of credibility influence and multi‐faceted. After a systematic evaluation, we found that these guidelines have both similarities and differences in terms of what organizations or bodies drafted the guidelines and the approach, applicability, content and recent updates of the guidelines as well as in terms of diagnostic and treatment algorithms. The differences could be attributed to various aetiological factors, high‐risk patients, health systems, health resources, medical technology, treatment choices and income levels in different countries. Besides, although the full implementation of guidelines could benefit clinicians, patients and authorities, there is still a gap between projected goals and implementation. The factors potentially influencing implementation are what organizations or bodies are drafting guidelines, content and emphasis, modification and consistency of guidelines. Comparative analysis suggested that countries pay close attention to targeted audiences, a basis in evidence, a basis in available resources, applicable patients and systematic evaluation when establishing and implementing domestic guidelines for HCC.

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Over the past few decades, the screening for and early diagnosis of hepatocellular carcinoma (HCC) has attracted attention worldwide, and especially in Asian countries such as Japan and China. Such approaches can help detecting HCC at an earlier stage when curable interventions can be offered to achieve long-term disease-free survival for patients. Biomarkers have been used to screen for and diagnose HCC in various countries. In Japan, the combined tests of des-γ-carboxyprothrombin (DCP) and α-fetoprotein (AFP) or Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) have been shown to achieve a high level of sensitivity and specificity. These tests have routinely been used to screen for HCC and are covered by Japan’s national health insurance. Due to the routine practice of screening for HCC among high-risk patients, HCC nodules have been detected in the early stages in more than 60% of patients in Japan. In contrast, although several remarkable advances in the management of HCC have been made in China over the past few decades, most HCC patients still present with advanced-stage disease. AFP is the only serum biomarker that has widely been used to screen for and diagnose HCC in China. In recent years, several molecular biological studies have further investigated the clinical usefulness of DCP, and they have found that it may facilitate the screening for and diagnosis of HCC and assist with the assessment of HCC progression. DCP can serve as a biomarker to detect HCC in an early stage and facilitate definitive treatment. The wide implementation of DCP is expected, especially in China where 55% of HCC cases worldwide live.