Chemotherapy with etoposide, doxorubicin, cisplatin, 5-fluorouracil, and leucovorin for patients with advanced hepatocellular carcinoma

Yuan, Jeng-Nian; Chao, Yee; Lee, Wei-Ping; Li, Chung–Pin; Lee, Rheun‐Chuan; Chang, Full‐Young; Yen, Sang‐Hue; Lee, Shou‐Dong; Whang‐Peng, Jacqueline

doi:10.1007/s12032-007-9013-3

Cited by 27 publications

(19 citation statements)

References 23 publications

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“…One of the most important problems that hamper the efficiency of cancer chemotherapeutic drugs, such as cisplatin and etoposide, is chemoresistance (15,16). Accumulated data strongly suggest a causal relationship between defects in apoptosis and drug resistance (17).…”

Section: Discussionmentioning

confidence: 99%

Etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells

Yoo

Yoon

Lee

et al. 2012

International Journal of Oncology

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Abstract. The Bcl-2 protein is known to exert not only antiapoptotic but also anti-autophagic activities. Numerous studies have demonstrated that etoposide, which is one of the most widely used cancer chemotherapy agents, induces apoptotic cell death. However, the exact molecular mechanism leading to cell death by etoposide remains to be resolved. This study aimed to dissect the mode of cell death induced by etoposide in Hep3B hepatoma cells. Furthermore, this study was conducted to examine whether etoposide overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells. We observed that Hep3B cells treated with etoposide show not only apoptotic but autophagic phenotypes. Autophagy inhibition by 3-methyladenine (3MA) and caspase inhibition by zVAD-fmk effectively decreased autophagic and apoptotic phenotypes, respectively. However, either zVAD-fmk or 3MA only partially prevented cell death. These data indicate that etoposide concomitantly induces autophagic cell death and apoptosis in Hep3B cells. Importantly, etoposide can effectively induce cell death in Bcl-2-overexpressing Hep3B cells. Conversely, staurosporine, which exclusively induces apoptosis in Hep3B cells, did not efficiently induce cell death in Bcl-2-overexpressing Hep3B cells. Staurosporine-treated Hep3B cells also showed an autophagic phenotype. While autophagy is cell death-inducing in Hep3B cells treated with etoposide, it is cytoprotective in Hep3B cells treated with staurosporine. To this end, we observed that etoposide-induced mixed type of programmed cell death is associated with the dissociation of Bcl-2 from Beclin-1. Taken together, etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells.

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Section: Discussionmentioning

confidence: 99%

Etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells

Yoo

Yoon

Lee

et al. 2012

International Journal of Oncology

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“…However, HCC is a weakly chemosensitive neoplasm, with a low response rate (about 15%) in single-agent phase II trials [3]. One of the most important problems that hamper the efficiency of cancer chemotherapeutic drugs, such as cisplatin [4] and etoposide [5], is the chemoresistance. To date, increasing efforts have been made to reveal the resistance mechanism and develop effective agents to evade the resistant apparatus.…”

Section: Introductionmentioning

confidence: 99%

“…Chemotherapeutic agents including etoposide and histone deacetylase inhibitors (HDACi) have been shown to inhibit HCC [5,17]. Etoposide, a podophyllotoxin semiderivative agent, is a widely used anti-cancer drug [18].…”

Section: Introductionmentioning

confidence: 99%

Trichostatin A sensitizes HBx-expressing liver cancer cells to etoposide treatment

Zhang

Chen

et al. 2011

Apoptosis

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Agents commonly used in cancer chemotherapy rely on the induction of cell death via apoptosis, mitotic catastrophe, premature senescence and autophagy. Chemoresistance is the major factor limiting long-term treatment success in patients with hepatocellular carcinoma (HCC). Recent studies have revealed that the hepatitis B virus X protein (HBx) exerts anti-apoptotic effects, resulting in an increased drug resistance in HCC cells. In this study, we showed that etoposide treatment activated caspase-8 and caspase-3, leading to cleavages of p53, Bid and PARP, which subsequently induced apoptosis. Furthermore, p53 and Bid were accumulated in cytoplasm following etoposide treatment. However, HBx significantly attenuated etoposide-induced cell death. In HBx-expressing cells, despite the translocation of p53 and Bid to cytoplasm, the activation of caspases was inhibited. Furthermore, the phosphorylation of extracellular-signal-regulated kinase (ERK) was markedly increased in HBx-expressing cells. Moreover, the pretreatment with trichostatin A (TSA, a histone deacetylase inhibitor) or TSA in combination with etoposide significantly sensitized HCC cells to apoptosis by inhibiting ERK phosphorylation, reactivating caspases and PARP, and inducing translocation of p53 and Bid to cytoplasm. Collectively, HBx reduces the sensitivity of HCC cells to chemotherapy. TSA in combination with etoposide can significantly overcome the increased resistance of HBx-expressing HCC cells to chemotherapy.

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“…23 There are various studies in respect of the usefulness of etoposide in HCC treatment. 24 Etoposide causes apoptosis by interacting with topoisomerase II. 25 Also, by increasing the reactive oxygen species (ROS) quantity, it also causes apoptosis by protein kinase C delta (PKCδ), p38 MAPK and caspase-3 stimulation.…”

mentioning

confidence: 99%

The Role of Acetylsalicylic Acid as an Assistant Drug in the Management of Hepatocellular Carcinoma

Alaçam¹

2012

UHOD

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Glucose regulated protein 78 (Grp78) is a chaperon which acts in the protein folding. Cell-surface Grp78 is present on the surface of different type cancer cells. There are evidences that acetylsalicylic acid (ASA) provides advantages when combined with other chemotherapeutic agents in cancer patients. Resistance is an important problem in cancer treatment and etoposide is a drug which develops resistance against itself. Our purpose in this study is to see how the ASA, either used alone or combined with etoposide, affect on the HepG2 cell viability and to investigate the relationship of this viability with the cell-surface Grp78. Thus 12 different groups were assigned. Control group, 0.5 µg/ml etoposide group, 2.5, 5, 10 mM ASA groups, 10 mM 2-deoxyglucose (2-DG) + 0.5 µg/ml etoposide group and the groups added to this group with 2.5, 5 and 10 mM ASA respectively, 10 mM 2-DG +2.5 mM ASA group, 10 mM 2-DG + 5 mM ASA group, 10 mM 2-DG + 10 mM ASA group. MTT test was applied for the follow up of the viability of the cells. When the viability in etoposite group was %84.5, the viability in 2-DG+etoposit group was %75.4. This shows that 2-DG decreases the viability of the cells a little. Also, when ASA is applied alone or combined with 2-DG, it caused decrease in the cell viability but this effect was more significant when combined with 2-DG. When etoposide and ASA were combined, the decrease in high-dose viability was more significant. Cell surface Grp78 levels were higher in the group in which 2-DG and ASA were combined each other than the group in which ASA was applied alone. All these results show that cell-surface Grp78 is important for ASA showing its effect. New treatment protocols focused on the cell-surface Grp78 in cancer treatment can be revealed by further studies.Keywords: Grp78, Cell-surface Grp78, HepG2, Etoposide, Acetylsalicylic acid ÖZET Hepatosellüler Karsinoma Tedavisinde Yard›mc› bir ‹laç Olarak Asetilsalisilik Asit'in RolüGlucose regulated protein 78 (Grp78) protein katlanmas›nda rol oynayan bir flaperondur. Cell-surface Grp78 farkl› türde kanser hüc-relerinin yüzeyinde bulunmaktad›r. Acetylsalicylic acid (ASA)'n›n kanser hastalar›nda kullan›m›n›n fayda sa¤lad›¤›na dair kan›tlar vard›r. Kanser tedavisinde direnç önemli bir problemdir ve etoposide kendisine direnç geliflen bir ilaçt›r. Bizim bu çal›flmadaki amac›m›z etoposide ile kombine olarak ya da tek bafl›na kullan›lan ASA'n›n HepG2 hücre viabilitesi üzerine nas›l etki etti¤ini görmek ve bu canl›l›-¤›n cell-surface Grp78 ile iliflkisini araflt›rmakt›r. Bu amaçla 12 farkl› grup oluflturuldu. Kontrol grubu, 0.5 µg/ml etoposid grubu, 2.5, 5, 10 mM ASA gruplar›, 10 mM 2-deoxyglucose (2-DG) + 0.5 µg/ml etoposid içeren grup ve bu gruba s›ras›yla 2.5, 5 ve 10 mM ASA eklenen gruplar, 10 mM 2-DG +2.5 mM ASA grubu, 10 mM 2-DG + 5 mM ASA grubu, 10 mM 2-DG + 10 mM ASA grubu. Hücre-lerin canl›l›klar›n›n izlenmesi içinde MTT testi yap›ld›. Sadece etoposit verilen grupta canl›l›k %84.5 iken, 2-DG+etoposit verilen grupta canl›l›k %75.4 kadard›. 2-DG'n...

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Chemotherapy with etoposide, doxorubicin, cisplatin, 5-fluorouracil, and leucovorin for patients with advanced hepatocellular carcinoma

Abstract: Triweekly EAPFL chemotherapy is a moderately effective regimen with tolerable toxicities in the treatment of advanced HCC.

Cited by 27 publications

References 23 publications

Etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells

Etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells

Trichostatin A sensitizes HBx-expressing liver cancer cells to etoposide treatment

The Role of Acetylsalicylic Acid as an Assistant Drug in the Management of Hepatocellular Carcinoma

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