Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners

Chiba, Tetsuhiro; Suzuki, Eiichiro; Yuki, Kaori; Zen, Yoh; Oshima, Motohiko; Miyagi, Satoru; Saraya, Atsunori; Koide, Shuhei; Motoyama, Tenyu; Ogasawara, Satoshi; Ooka, Yoshihiko; Tawada, Akinobu; Nakatsura, Tetsuya; Hayashi, Takuo; Yamashita, Taro; Kaneko, Shuya; Miyazaki, Masaru; Iwama, Atsushi; Yokosuka, Osamu

doi:10.1371/journal.pone.0084807

Cited by 71 publications

(54 citation statements)

References 31 publications

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“…Normally, p38 MAPK activities are significantly lower in HCC, while the activation of p38 MAPK may cause apoptosis of HCC cells (28). Previous studies have demonstrated that certain toxic agents induce cell apoptosis via activation of p38 MAPK (29). The present findings revealed that HP induced cell cycle arrest and apoptosis, and activated the three major MAPK pathways in HCC cells, although the expression of p38 MAPK significantly increased compared with that of JNK and ERK.…”

Section: Discussionmentioning

confidence: 39%

Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MAPK

et al. 2016

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Abstract. The underlying mechanism of the antitumor activity of Huaier polysaccharide (HP) remains to be explored. The present study aimed to investigate the inhibitory effect of HP on hepatocellular carcinoma (HCC) cells, and to explore the possible mechanisms of its anticancer effect. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, while apoptotic nuclear changes were observed using Hoechst 33258 staining. The distribution of cell cycle and apoptosis were analyzed by flow cytometry, and western blotting was used to test the apoptotic pathways. Apoptosis and mitogen-activated protein kinase (MAPK) inhibitors were used to investigate the mechanism of apoptosis. HP triggered cell cycle arrest and apoptosis in HepG2 and Huh7 cells. Both the extrinsic and intrinsic apoptotic pathways were activated after HP treatment. Furthermore, HP enhanced the three major MAPK pathways (extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38 MAPK) and inhibited the AKT/mechanistic target of rapamycin signaling pathway in HCC cells. Notably, the inactivation of p38 MAPK impaired the HP-induced cell death. HP exerted its antitumor effect on HCC cells through the regulation of the expression of the apoptosis-related proteins B-cell lymphoma (Bcl)-2, Bcl-2-associated X protein and survivin. The present study provides evidence that HP induces apoptosis in HCC cells and demonstrated the role of p38 MAPK in HP-triggered cancer cell death. IntroductionLiver cancer, particularly hepatocellular carcinoma (HCC), is one of the most common human malignancies with poor long-term survival rates (1-3). Although liver transplantation, hepatectomy and local therapy are potentially curative therapies in the early stages of HCC (4,5), the majority of patients, who are usually diagnosed at an advanced stage, must rely mainly on traditional chemotherapies (6,7). Currently, there is no proven effective conventional systemic chemotherapy for patients with advanced HCC (7). Therefore, novel therapeutic agents with high efficacy are urgently required for the clinical treatment of advanced HCC.Trametes robiniophila Murr (Huaier) is a type of fungus that exists in China, and previous chemical analyses revealed that Huaier consists mainly of polysaccharide (8). Recent studies have noticed that Huaier polysaccharide (HP) exerts a pro-apoptotic effect on the cells of a variety of human cancers, including breast cancer (9,10), hepatocarcinoma (11-14), lung adenocarcinoma (15) and ovarian cancer (16). In addition, Huaier and HP suppress cancer cell metastasis and motility (12,16,17), exhibit anti-angiogenic activity and enhance the host immune system function (11,14,18). Together, these data indicate that HP exhibits promising results against cancer in pre-clinical trials.The use of Huaier has been approved by the Chinese Food and Drug Administration for the clinical treatment of patients with malignant tumors (China Food and Drug Administration approval number, Z20000109; http://app1.sfda.gov.cn...

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Section: Discussionmentioning

confidence: 39%

Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MAPK

et al. 2016

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“…In vitro evidence also supports the ability of disulfiram and liposome-encapsulated disulfiram to eradicate CSCs and resistant cells in different tumor types, including breast [41], hepatocellular [45], lung [46], pancreatic [47], and lymphoid [48] carcinomas. Currently, trials are underway to determine the optimal doses at which its safety profile can be maintained (hepatotoxicity has been observed at high doses), to exploit the highest tumor cell response, and to investigate its combination with other drugs (e.g., copper supplements) (Table 1), as well as the definition of its in vivo mechanism of action [49].…”

Section: Disulfirammentioning

confidence: 71%

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds

Würth

Thellung

Bajetto

et al. 2016

Drug Discovery Today

124

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“…The protective efects of ALDH for CSCs may also include the inhibition of downstream apoptosis-related pathways [18,23,24]. ALDH-positive CSCs have also demonstrated resistance to myriad chemotherapeutic agents such as anthracyclines and taxanes [25,26], two classes of drugs commonly used in OS treatment.…”

Section: Osteosarcoma -Biology Behavior and Mechanisms 34mentioning

confidence: 99%

The Use of Molecular Pathway Inhibitors in the Treatment of Osteosarcoma

Mahjoub¹,

Crasto²,

Mandell³

et al. 2017

Osteosarcoma - Biology, Behavior and Mechanisms

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Presently, the 5-year survival rate for metastatic osteosarcoma remains low despite advances in chemotherapeutics and neoadjuvant therapy. A majority of the morbidity and nearly all of the mortality in osteosarcoma rely not in the primary disease but in the metastatic disease. The pursuit of novel molecular therapies is atractive due to their targeted ability to combat metastasis. Unlike traditional chemotherapy agents, which work by targeting rapidly dividing cells, targeted therapies may spare normal cells and decrease the adverse efects of chemotherapy by targeting speciic pathways. Here, we discuss key molecular pathways in osteosarcoma and their ability to be modulated for the goal of eradication of primary and metastatic disease. We focus speciically on the aldehyde dehydrogenase (ALDH), epidermal growth factor receptor (EGFR), and insulin-like growth factor-1 receptor (IGF-1R) pathways.

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Disulfiram Eradicates Tumor-Initiating Hepatocellular Carcinoma Cells in ROS-p38 MAPK Pathway-Dependent and -Independent Manners

Cited by 71 publications

References 31 publications

Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MAPK

Huaier polysaccharide induces apoptosis in hepatocellular carcinoma cells through p38 MAPK

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds

The Use of Molecular Pathway Inhibitors in the Treatment of Osteosarcoma

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