Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight

Lohitesh, K.; Chowdhury, Rajdeep; Mukherjee, Sudeshna

doi:10.1186/s12935-018-0538-7

Cited by 208 publications

(168 citation statements)

References 145 publications

(106 reference statements)

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“…However, patients with Hcc treated with dox or sorafenib exhibit resistance to chemotherapy (34). epigenetic alterations, cellular export of drugs and evasion of apoptosis are frequently identified in resistant Hcc cells, and these processes markedly limit the effectiveness of chemotherapy (35). Therefore, it is necessary to develop novel strategies to improve the effect of chemotherapy and prevent chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis

Xia¹,

Zeng²,

Zheng

2020

Mol Med Report

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Hepatocellular carcinoma (Hcc) is a type of liver cancer and is a leading cause of cancer-associated mortality. in china, ~466,000 patients are diagnosed with Hcc and it is responsible for ~422,000 cases of mortality each year. Surgery is the most effective treatment available; however it is only suitable for patients with early-stage Hcc. chemotherapy has been confirmed as a necessary treatment for patients with advanced Hcc, although drug resistance may limit its clinical outcome. low intensity ultrasound (liuS) represents a novel therapeutic approach to treat patients with Hcc; however, its underlying molecular mechanism remains unclear. in the present study, cell viability, apoptosis and reactive oxygen species (roS) generation were determined via cell counting Kit-8, flow cytometry and 2',7'-dichlorofluorescein diacetate assays, respectively. The expression of mirna in Hcc cells following exposure to liuS and doxorubicin (dox) was analyzed using a microarray and reverse transcription-quantitative polymerase chain reaction analysis. it was revealed treatment with liuS in combination with dox was able to induce apoptosis of Huh7 cells, increasing the intracellular levels of reactive oxygen species (roS) and malondialdehyde. Glutathione peroxidase and superoxide dismutase 1 are roS-scavenging enzymes, which serve important roles in the oxidative balance, preventing oxidative stress. The protein expression levels of these two enzymes were significantly decreased following treatment with liuS combined with dox. The present results suggested that liuS may decrease dox resistance in Hcc cells and that liuS may be combined with chemotherapy to treat Hcc. By performing microarray analysis, the expression levels of microrna-21 (mir-21) were decreased following treatment with liuS combined with dox. Functional experiments showed that knockdown of mir-21 enhanced the antitumor activity of dox, whereas overexpression of mir-21 reversed these effects. Phosphatase and tensin homolog (PTen), a well-known tumor suppressor, was revealed to be a direct target of mir-21, and its translation was suppressed by mir-21. Finally, it was determined that combined treatment of liuS and dox induced anticancer effects by blocking the activation of the aKT/mTor pathway, as demonstrated by the downregulation of phosphorylated (p-)aKT and p-mTor; n-acetylcysteine, a general roS inhibitor reversed the suppressive effects on the aKT/mTor pathway mediated by liuS and dox. collectively, the present results suggested that liuS increased cell sensitivity to dox via the roS/mir-21/PTen pathway. chemotherapy combined with liuS may represent a novel effective therapeutic strategy to treat patients with advanced Hcc.

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Section: Discussionmentioning

confidence: 99%

Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis

Xia¹,

Zeng²,

Zheng

2020

Mol Med Report

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“…It also has various side effects including alopecia, arthralgia, diarrhea, fatigue, headache and hypertension [5,6]; improved therapeutic strategies are thus urgently needed. The other major problem in the treatment of HCC is the onset of resistance to chemotherapeutic drugs, and even multi-drug resistance [7,8].…”

Section: Introductionmentioning

confidence: 99%

Impaired Anti-Tumor T cell Response in Hepatocellular Carcinoma

Chaoul

Mancarella

Lupo

et al. 2020

Cancers

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Different subsets of lymphocytes have the capacity to promote or counteract the progression of solid cancers, including hepatocellular carcinoma (HCC). Therefore, to determine the infiltrative ability and functional status of major immune cell subtypes into tumor may lead to novel insights from the perspective of immunotherapy. After obtaining single cell suspensions from freshly collected specimens of HCC tumor, along with paired peritumor tissues and peripheral blood mononuclear cells (PBMCs) from 14 patients, we flow-cytometrically identified and quantified the relative frequencies of lymphocyte subsets within the tissues of origin. We found that the recruitment in the tumor of cytotoxic cells, namely the terminally differentiated CD4+ and CD8+ T cells (TEFF), is impaired, whereas the effector memory CD4+ T cells (TEM) are more attracted in this site. Concerning the other subsets, the frequency of NK CD56hi and NKT CD56hi cells infiltration in the tumor is increased, whereas that of NKT CD56low is reduced. Although CD4+ and CD8+ T cells settled in the tumor show a higher degree of activation than the circulating counterpart, they occur with a more exhausted phenotype. Overall, these data demonstrate the prevalently immunosuppressive nature of HCC microenvironment, and prompt us to search for strategies to enhance the activity of anti-tumor immune cell subsets.

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“…6 and Supplementary Figs. 4,5). Notably, clusters of GADD153/CHOP positivity were observed in the nucleus of cells treated with 250 ( Supplementary Fig.…”

Section: α-La-treated Fao Cells Show Dysregulation Of Genes Involvedmentioning

confidence: 91%

α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells

Pibiri

Sulas

Camboni

et al. 2020

Sci Rep

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Hepatocellular carcinoma (Hcc) is the most common liver cancer and a major cause of adult death. the current treatments for HCC suffer from drug resistance and poor prognosis; therefore, novel therapeutic agents are urgently needed. Phytochemicals have been proposed to treat a range of cancers. Among them, α-lipoic acid (α-LA), a naturally synthesized antioxidant found in various dietary animal and plant sources, prevents oxidant-mediated cell death in normal cells while inducing apoptosis in several cancer cell lines. Previously, we demonstrated that the treatment of hepatoma cells with α-LA induced apoptosis, which was preceded by the generation of reactive oxygen species (ROS) and activation of the p53 protein, a known inducer of mitochondria-mediated apoptosis. Several studies have shown that ROS-induced apoptosis is associated with endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) activation. Herein, we investigated if α-LA-induced apoptosis in hepatoma cell lines was ER stress-and UPR-mediated by gene expression profiling analyses. UPR and ER stress pathways were the most up-regulated after treatment with α-LA. This finding, which has been confirmed by expression analyses of ER-and UPR-associated proteins, provides a better understanding of the molecular mechanisms behind the anti-tumoral action of α-LA on hepatoma cells.

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Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight

Cited by 208 publications

References 145 publications

Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis

Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis

Impaired Anti-Tumor T cell Response in Hepatocellular Carcinoma

α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells

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