Synergistic Sorafenib with Jianpi Huayu Decoction Resulted in Tumor Regression and Prevented Adverse Events in Hepatocellular Carcinoma by Remodeling the Gut Microbiota

Abstract Background: There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Sorafenib is first-line treatment for HCC, which has a modest efficacy due to severe adverse effects(AE), acquired resistance and others. Combination therapy may be able to overcome this limitation. Jianpi Huayu Decoction (JHD) is a traditional Chinese medicine formulation, which has been shown to be effective as an alternative and complementary therapy of HCC. We investigated the synergistic effect of JHD with sorafenib by a xenograft model.Methods: Growth of mouse-derived HCC cells and adverse events(AE) of treatment were evaluated in a subcutaneous model with JHD and clinical-dose sorafenib combination treatment. Diarrhea, the most frequently reported AE, was evaluated by diarrhea score. The gut microbiota(GM) composition of the mice was analyzed by Illumina NovaSeq. Results: JHD administration in mice synergistically enhanced the anti-tumor response, thereby suppressing HCC, and prevented occurrence of the most common AEs(diarrhea and body weight loss) of sorafenib. Sorafenib induced increased proinflammatory GM(Helicobacter) which promoted the progression of HCC and against anti-tumor treatment. JHD reduced the abundance of anti-inflammatory microbiota Muribaculum, Fusicatenibacter, and Dorea. Following the modulation of GM, the proinflammatory signaling interleukin 6/signal transducer and activator of transcription-3 pathway was downregulated by JHD.Conclusions: Our finding suggested that differences in the microbial gut flora may modulate resistance to sorafenib through IL-6/STAT3 signaling. JHD with microbiota modulation properties could potentiate sorafenib and provided a promising approach for HCC treatment.

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MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1

Cell Death and Disease ◽

10.1038/s41419-021-04491-0 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Zhe-bin Dong ◽

Heng-miao Wu ◽

Yi-cheng He ◽

Zhong-ting Huang ◽

Yi-hui Weng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Acquired Resistance ◽

Xenograft Model ◽

Early Recurrence ◽

Advanced Hepatocellular Carcinoma ◽

Curative Surgery ◽

Multikinase Inhibitor ◽

Key Factor ◽

Nuclear Location ◽

Induced Apoptosis

AbstractAs a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

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Treatment with a new benzimidazole derivative bearing a pyrrolidine side chain overcomes sorafenib resistance in hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-019-53863-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Fat-Moon Suk ◽

Chao-Lien Liu ◽

Ming-Hua Hsu ◽

Yu-Ting Chuang ◽

Jack P. Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Benzimidazole Derivative ◽

Acquired Resistance ◽

Xenograft Model ◽

Side Chain ◽

Mesenchymal Transition ◽

New Compounds ◽

Line Drug

AbstractHepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Currently, sorafenib is the standard first-line drug for patients with advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity of tumour cells to the drug, leading to acquired resistance. Therefore, developing new compounds to treat sorafenib resistance is urgently needed. Although benzimidazole and its derivatives have been reported to exert antimicrobial and antitumour effects, the anti-drug resistance potential of these molecules is still unknown. In this study, we established sorafenib-resistant (SR) cell lines and an acquired sorafenib resistance xenograft model. We showed that treatment with a benzimidazole derivative bearing a pyrrolidine side chain (compound 9a) inhibited the proliferation of SR cells by blocking the phosphorylation of AKT, p70S6 and the downstream molecule RPS6. In addition, caspase 3/PARP-dependent apoptotic signals were induced in 9a-treated cells. Regarding epithelial-mesenchymal transition (EMT) activities, 9a treatment significantly suppressed the migration of SR cells. In particular, the levels of EMT-related transcription factors (snail, slug and twist) and mesenchymal markers (vimentin and N-cadherin) were downregulated. In the acquired sorafenib resistance xenograft model, compound 9a administration decreased the growth of tumours with acquired sorafenib resistance and the expression of the HCC markers α-fetoprotein, glypican 3 and survivin. In conclusion, treatment with this compound may be a novel therapeutic strategy for patients with sorafenib resistance.

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YM155, a Novel Survivin Suppressant, Improves the Antitumor Effect of Rituximab and Rituximab-Containing Regimens in Diffuse Large B Cell Lymphoma (DLBCL) Xenograft Mouse Models.

Blood ◽

10.1182/blood.v114.22.2718.2718 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2718-2718

Author(s):

Mari Nakata ◽

Takahito Nakahara ◽

Aya Kita ◽

Keisuke Mitsuoka ◽

Kentaro Yamanaka ◽

...

Keyword(s):

Antitumor Effect ◽

Cell Lymphoma ◽

Tumor Regression ◽

Xenograft Model ◽

Body Weight Loss ◽

B Cell Lymphoma ◽

In Vivo Studies ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Abstract 2718 Poster Board II-694 Introduction: Survivin is a member of the inhibitor of apoptosis (IAP) family of proteins, and is highly expressed in many tumor types. Given its preferential expression in tumor cells, and its ability to block apoptosis and regulate cancer cell proliferation, survivin appears to be an attractive novel target for cancer therapy. YM155 is a novel, small molecule survivin suppressant (Nakahara et al., Cancer Research. 2007;67:8014–21). In this study, we evaluated the antitumor activity of YM155 alone and in combination with rituximab, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), or [rituximab + cytarabin + cisplatin] in DLBCL xenograft models. Methods: Antiproliferative effect of YM155 in a panel of human DLBCL cell lines (DB, Pfeiffer, SU-DHL5, SU-DHL8, WSU-DLCL-2, and RL) was evaluated by sulforhodamine B assay. In in vivo studies, WSU-DLCL-2 and DB were subcutaneously implanted into male BALB/c nu/nu mice. When tumors reached a volume of 300 to 600 mm3, YM155 was administered as a 7-day continuous sc infusion, and the other drugs were administered via iv bolus. Dose and schedule of each drug were adjusted to clinical equivalent dose. PET imaging studies were performed using a Inveon PET/CT system (Siemens Medical Solusion). WSU-DLCL-2 xenografted mice were intravenously injected with [18F] FLT, and five-minute static PET scans were accqiured at 1h after injection. For each small-animal PET scan, region of interest was drawn over each tumor and over normal tissue on decay-corrected whole-body sagittal imagies. Results: In in vitro proliferation assays, YM155 showed potent antiproliferative activity against all six DLBCL cell lines, with GI50 values of 0.35 to 3.9 nM. In in vivo studies using WSU-DLCL2 xenograft model, YM155 at 1 and 3 mg/kg induced tumor regression without body weight loss. In combination studies using WSU-DLCL2 xenograft model, YM155 2 mg/kg enhanced antitumor effects of rituximab, R-ICE and [rituximab + cytarabin + cisplatin] without enhancement of the body weight loss. Tumor regression in the combination groups was sustained longer than single treatment groups, and even complete regressions were achievable. Moreover, combination of YM155 1 mg/kg and rituximab induced strong tumor regression in the DB xenograft model, while single-agent treatments did not show significant antitumor effect compared to vehicle control. In [18F]FLT-PET imaging, a significant reduction of FLT uptake in tumor was observed in rituximab combination group, which was more sensitive than the reduction in tumor volume. Conclusions: YM155 improves the antitumor effect of rituximab and rituximab-containing regimens in diffuse large B cell lymphoma (DLBCL) xenograft mouse models. Disclosures: Nakata: Astellas Pharma Inc.: Employment. Nakahara:Astellas Pharma Inc.: Employment. Kita:Astellas Pharma Inc.: Employment. Mitsuoka:Astellas Pharma Inc.: Employment. Yamanaka:Astellas Pharma Inc.: Employment. Kaneko:Astellas Pharma Inc.: Employment. Miyoshi:Astellas Pharma Inc.: Employment. Mori:Astellas Pharma Inc.: Employment. Koutoku:Astellas Pharma Inc.: Employment. Sasamata:Astellas Pharma Inc.: Employment.

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miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells

Cell Death and Disease ◽

10.1038/s41419-019-2053-8 ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 14

Author(s):

Yue Zhou ◽

Enjiang Chen ◽

Yuexiao Tang ◽

Jiayan Mao ◽

Jian Shen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Acquired Resistance ◽

Xenograft Model ◽

Term Therapy ◽

Autophagic Flux ◽

Doxorubicin Resistance ◽

Novel Mirna ◽

Mouse Xenograft Model ◽

Hcc Cells

Abstract Doxorubicin is conventionally used in chemotherapy against hepatocellular carcinoma (HCC), but acquired resistance developed during long-term therapy limits its benefits. Autophagy, a conserved catabolic process for cellular self-protection and adaptation to the changing environment, is regarded as a potential clinical target to overcome doxorubicin resistance. In this study, the potential role of miR-223 in modulating doxorubicin-induced autophagy and sensitivity were evaluated in four transfected human HCC cell lines, and the in vivo relevance was assessed using a mouse xenograft model of HCC. We found that the well-defined miR-223 is expressed at low levels in doxorubicin treated HCC cells and that miR-223 overexpression inhibits the doxorubicin-induced autophagy that contributes to chemoresistance. Blockade of autophagic flux by chloroquine resulted in the failure of miR-223 inhibitor to suppress doxorubicin sensitivity of HCC cells. We further identified FOXO3a as a direct downstream target of miR-223 and primary mediator of the regulatory effect of miR-223 on doxorubicin-induced autophagy and chemoresistance in HCC cells. Finally, we confirmed the enhancement of doxorubicin sensitivity by agomiR-223 in xenograft models of HCC. These findings establish a novel miRNA-based approach for autophagy interference to reverse doxorubicin resistance in future chemotherapy regimens against human HCC.

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Combination therapy with lenvatinib and anti-PD-1 antibodies for unresectable or advanced hepatocellular carcinoma: A real-world study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16610 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16610-e16610

Author(s):

Hui-Chuan Sun ◽

Xiao-Dong Zhu ◽

Cheng Huang ◽

Ying-Hao Shen ◽

Ning-Ling Ge ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Combination Therapy ◽

Adverse Events ◽

Combination Treatment ◽

Tumor Regression ◽

R0 Resection ◽

Advanced Hepatocellular Carcinoma ◽

First Line ◽

Angiogenic Therapy ◽

First Line Therapy

e16610 Background: Combination therapy of anti-angiogenic therapy and anti-PD-1 antibody had shown promising anti-tumor effects for advanced hepatocellular carcinoma (HCC) in clinical trials. Here we report the effectiveness and safety of the combination therapy of lenvatinib and anti-PD-1 antibodies in a cohort of unresectable or advanced HCC pts. Methods: From Sep 2018 to Jan 2020, 77 consecutive pts received a combination treatment of lenvatinib and an anti-PD-1 antibody. Lenvatinib was given 8 mg/d regardless of patient body weight and anti-PD-1 antibody was used either q2wk (nivolumab or camrelizumab) or q3wk (pembrolizumab, sintilimab or toripalimab). pts who completed at least one efficacy and safety assessment were eligible for this study. Tumor response were evaluated with abdominal contrast-enhanced MRI/CT and/or chest CT every 2 mo (± 1 wk). Laboratory tests were monitored every 2-3 wk. Results: 59 pts were eligible for this study. Of them, 1 (1.7%) were BCLC stage A, 10 (16.9%) were BCLC stage B, 48 (81.4%) were BCLC stage C (including 20 pts in China Liver Cancer [CNLC] stage IIIa and 28 in CNLC stage IIIb). 43 (72.9%) pts were treated as first-line therapy. The table below shows efficacy results. R0 resection was performed in 6 (10.2%) pts due to tumor regression. By the data cut-off date, 13 pts died, and mOS was not mature. Overall, the combination treatment was well tolerated. 28 (47.5%) pts had at least one ≥ grade 3 treatment-emergent adverse event. 3 (5.1%) pts died from immune-related adverse events, 2 of them died from immune-related adverse events after hepatectomy. Conclusions: The combination of lenvatinib + anti-PD-1 antibody is effective and well-tolerated in pts with HCC as first-line or second-line treatment. It is also noted that initially unresectable HCC may be converted to resectable HCC following this combination treatment. [Table: see text]

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Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma

Cell Death and Disease ◽

10.1038/s41419-019-1989-z ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 15

Author(s):

Jacopo Gavini ◽

Noëlle Dommann ◽

Manuel O. Jakob ◽

Adrian Keogh ◽

Laure C. Bouchez ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Antitumor Effect ◽

Acquired Resistance ◽

Xenograft Model ◽

Resistance Mechanisms ◽

Chemotherapeutic Agents ◽

Anti Cancer

Abstract Lysosomal sequestration of anti-cancer compounds reduces drug availability at intracellular target sites, thereby limiting drug-sensitivity and inducing chemoresistance. For hepatocellular carcinoma (HCC), sorafenib (SF) is the first line systemic treatment, as well as a simultaneous activator of autophagy-induced drug resistance. The purpose of this study is to elucidate how combination therapy with the FDA-approved photosensitizer verteporfin (VP) can potentiate the antitumor effect of SF, overcoming its acquired resistance mechanisms. HCC cell lines and patient-derived in vitro and in vivo preclinical models were used to identify the molecular mechanism of action of VP alone and in combination with SF. We demonstrate that SF is lysosomotropic and increases the total number of lysosomes in HCC cells and patient-derived xenograft model. Contrary to the effect on lysosomal stability by SF, VP is not only sequestered in lysosomes, but induces lysosomal pH alkalinization, lysosomal membrane permeabilization (LMP) and tumor-selective proteotoxicity. In combination, VP-induced LMP potentiates the antitumor effect of SF, further decreasing tumor proliferation and progression in HCC cell lines and patient-derived samples in vitro and in vivo. Our data suggest that combination of lysosome-targeting compounds, such as VP, in combination with already approved chemotherapeutic agents could open a new avenue to overcome chemo-insensitivity caused by passive lysosomal sequestration of anti-cancer drugs in the context of HCC.

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SHC4 promotes tumor proliferation and metastasis by activating STAT3 signaling in hepatocellular carcinoma

Cancer Cell International ◽

10.1186/s12935-022-02446-9 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Xin Zhang ◽

Hongwei Zhang ◽

Zhibin Liao ◽

Jiacheng Zhang ◽

Huifang Liang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Western Blotting ◽

Colony Formation ◽

Xenograft Model ◽

Adaptor Protein ◽

Migration And Invasion ◽

Stat3 Signaling ◽

Hcc Cells

Abstract Background The Src homology and collagen 4 (SHC4) is an important intracellular adaptor protein that has been shown to play a pro-cancer role in melanoma and glioma. However, the biological function and detailed mechanisms of SHC4 in hepatocellular carcinoma progression are unclear. This study aimed to evaluate the potential prognostic and treatment value of SHC4 in patients with HCC. Methods The expression status of SHC4 in HCC tissues were investigated by immunohistochemistry and western blotting. Clinical significance of SHC4 was evaluated in a large cohort of HCC patients. The effects of SHC4 repression or overexpression on migration, invasion, and tumor growth were detected by colony formation assay, wound healing, transwell assays, and xenograft assay. Cell cycle and EMT-related proteins were detected by western blotting and immunofluorescence. In addition, the molecular regulation between SHC4 and STAT3 signaling in HCC were discovered by western blotting, immunofluorescence and xenograft assay. Results SHC4 was overexpressed in HCC compared to adjacent normal liver tissues and increased SHC4 expression was associated with high AFP level, incomplete tumor encapsulation, poor tumor differentiation and poor prognosis. SHC4 was shown to enhance cell proliferation, colony formation, cells migration and invasion in vitro, and promotes cell cycle progression and EMT process in HCC cells. Tumor xenograft model assay confirmed the oncogenic role of SHC4 in tumorigenicity in nude mice. Moreover, activation of STAT3 signaling was found in the SHC4 overexpressed HCC cells and HCC tissues. Further intervention of STAT3 confirmed STAT3 as an important signaling pathway for the oncogenic role of SHC4 in HCC. Conclusions Together, our results reveal that SHC4 activates STAT3 signaling to promote HCC progression, which may provide new clinical ideas for the treatment of HCC.

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