Combination of anlotinib and gemcitabine promotes the G0/G1 cell cycle arrest and apoptosis of intrahepatic cholangiocarcinoma <i>in vitro</i>

Fan, Shanshan; Ge, Yang; Liu, Jian; Liu, Heshu; Yan, Rui; Gao, Tianbo; Fan, Xin; Xiao, Zeru; An, Guangyu

doi:10.1002/jcla.23986

Cited by 17 publications

(6 citation statements)

References 24 publications

(59 reference statements)

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“…Recent preclinical study has demonstrated synergistic cytotoxic effects of anlotinib in combination with the chemotherapeutic drug 5-FU against small cell lung cancer, both in vitro and in vivo(28). The combination of anlotinib and gemcitabine signi cantly inhibited the growth of ICC cells and induced cell apoptosis (29). In addition, anlotinib inhibited the proliferation, migration and invasion of BRCA cells and induce cell apoptosis by downregulating TFAP2C (30).…”

Section: Discussionmentioning

confidence: 98%

Synergistic effects of anlotinib and DDP synergy in breast cancer treatment: inhibiting of cell growth and migration, and augmenting apoptosis and autophagy via modulation of the VEGF/JAK2/STAT3 axis

Zhang,

Liu,

Jin

et al. 2024

Preprint

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Anlotinib has been shown to have good anti-tumor effects in a variety of tumors, including breast cancer (BRCA); however, the combined anti-tumor efficacy of anlotinib and DDP in BRCA, as well as the underlying mechanism, remain to fully elucidated. This study aims to explore the role of VEGFA expression in BRCA and the therapeutic efficacy of anlotinib, alone and in combination with cisplatin (DDP), in treating BRCA. BRCA cells were treated with or without anlotinib and/or DDP. The proliferation, migration and invasion capabilities of BRCA cells were evaluated using CCK-8 assays, clone formation assays, wound healing assays and transwell assays. Cell apoptosis was detected by Hoechst33342 fluorescence staining and flow cytometry technique. The potential mechanism of anlotinib in the development of BRCA was predicted through bioinformatics analysis, and the mRNA or protein levels were subsequently quantified using qPCR and western blot. The anti-breast cancer efficacy of anlotinib was evaluated in vivo using a xenograft tumor model. Our findings reveal that increased VEGFA expression in BRCA patients is associated with a poorer prognosis, underscoring the need for targeted therapeutic strategies. We demonstrate that both anlotinib and DDP independently inhibit BRCA cell growth, migration, and invasion. Their combination exhibits a synergistic effect, significantly enhancing the inhibition of these oncogenic processes. This synergy is further evident in the induction of apoptosis and autophagy within BRCA cells. Mechanistically, anlotinib's effectiveness is attributed to its inhibition of the JAK2/STAT3 pathway, a critical axis in BRCA progression. In vivo studies reinforce these findings, anlotinib markedly inhibits tumor growth in mice xenografted. This study confirms the efficacy of anlotinib or in combination with DDP and elucidates the mechanism behind anlotinib's effectiveness, highlighting its role in inhibiting the JAK2/STAT3 pathway. These findings pave the way for further clinical exploration and development of anlotinib-based therapies, offering hope for improved outcomes in breast cancer management.

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Section: Discussionmentioning

confidence: 98%

Synergistic effects of anlotinib and DDP synergy in breast cancer treatment: inhibiting of cell growth and migration, and augmenting apoptosis and autophagy via modulation of the VEGF/JAK2/STAT3 axis

Zhang,

Liu,

Jin

et al. 2024

Preprint

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“…To further investigate the efficacy of liensinine in treatment of ICC, we tried to combine liensinine with gemcitabine. Based on existing studies, 43–45 we set the concentration of gemcitabine on RBE and Hucc‐T1 to 10μM. Through colony formation test, wound healing assays, migration and invasion Transwell experiments, we found that, in RBE and Hucc‐T1 cells, liensinine combined with gemcitabine had certain curative effects on the proliferation, as well as on migration and invasion (Figures ).…”

Section: Discussionmentioning

confidence: 99%

“…Based on existing studies, [43][44][45] tumor resistance to gemcitabine, [46][47][48][49] and therapy targeting on HIF-1a may improve the efficacy of gemcitabine. 50,51 Besides, available data does not rule out the possibility that gemcitabine directly or indirectly acts on HIF-1a.…”

Section: Liensinine Reversed the Emt Phenotype Of Icc Cells With High...mentioning

confidence: 99%

Liensinine inhibits progression of intrahepatic cholangiocarcinoma by regulating TGF‐β1 /P‐smad3 signaling through HIF‐1a

Zhu,

Bao,

Xie

et al. 2024

Molecular Carcinogenesis

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Intrahepatic cholangiocarcinoma (ICC) is a high‐grade malignant digestive system tumor with an insidious onset and unfavorable prognosis. Liensinine, a small molecule derived from plants, has been proven to have significant tumor suppressor activity in other cancers. However, there are no reports on whether liensinine can inhibit the proliferation or metastasis of ICC. This study aimed to explore the tumor‐suppressive activity of liensinine in ICC and its underlying mechanisms. The phenotypic changes in ICC cells were monitored in vitro using cell function tests. Western blot and immunofluorescence analyses verified the efficacy of liensinine. Tumor‐bearing nude mice were used to explore the effect of liensinine on tumors and its toxicity and side effects in vivo. Liensinine suppressed ICC cell proliferation and arrested the cell cycle at the G1 phase. The epithelial‐mesenchymal transition (EMT) of ICC cells was also inhibited, thereby restraining their invasion and migration of tumor cells. In addition, this study found that the potential mechanism of liensinine inhibiting EMT may be via suppression of the TGF‐β1/P‐smad3 signaling pathway through hypoxia‐inducible factor 1 alpha (HIF‐1a). In vivo experiments showed that liensinine inhibited the growth of Hucc‐T1 transplanted tumors in nude mice. Liensinine restrained the proliferation of ICC cells and suppressed EMT in ICC via the HIF‐1a‐mediated TGF‐β1/P‐smad3 signaling pathway.

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“…The G1-phase cell cycle arrest observed at 5 μΜ concentration suggests a cell-cycle specific nature observed in Gem treatments. The cell cycle arrest at G1-phase revealed in our study could account for an increase in number of cells at the G1-phase which prevented the progression of cells into the S-phase to undergone DNA synthesis [ 57 ]. Previously, we demonstrated 4NSG’s ability to induce early apoptosis in pancreatic cancer cell at higher treatment concentrations [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Biological evaluation of novel gemcitabine analog in patient-derived xenograft models of pancreatic cancer

et al. 2023

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Gemcitabine (Gem) has been a standard first-line drug for pancreatic cancer (PCa) treatment; however, Gem's rapid metabolism and systemic instability (short half-life) limit its clinical outcome. The objective of this study was to modify Gem into a more stable form called 4-(N)-stearoyl-gemcitabine (4NSG) and evaluate its therapeutic efficacy in patient-derived xenograft (PDX) models from PCa of Black and White patients.Methods 4NSG was synthesized and characterized using nuclear magnetic resonance (NMR), elemental analysis, and high-performance liquid chromatography (HPLC). 4NSG-loaded solid lipid nanoparticles (4NSG-SLN) were developed using the cold homogenization technique and characterized. Patient-derived pancreatic cancer cell lines labeled Black (PPCL-192, PPCL-135) and White (PPCL-46, PPCL-68) were used to assess the in vitro anticancer activity of 4NSG-SLN. Pharmacokinetics (PK) and tumor efficacy studies were conducted using PDX mouse models bearing tumors from Black and White PCa patients.Results 4NSG was significantly stable in liver microsomal solution. The effective mean particle size (hydrodynamic diameter) of 4NSG-SLN was 82 ± 6.7 nm, and the half maximal inhibitory concentration (IC50) values of 4NSG-SLN treated PPCL-192 cells (9 ± 1.1 µM); PPCL-135 (11 ± 1.3 µM); PPCL-46 (12 ± 2.1) and PPCL-68 equaled to 22 ± 2.6 were found to be significantly lower compared to Gem treated PPCL-192 (57 ± 1.5 µM); PPCL-135 (56 ± 1.5 µM); PPCL-46 (56 ± 1.8 µM) and PPCL-68 (57 ± 2.4 µM) cells. The area under the curve (AUC), half-life, and pharmacokinetic clearance parameters for 4NSG-SLN were 3–fourfold higher than that of GemHCl. For in-vivo studies, 4NSG-SLN exhibited a two-fold decrease in tumor growth compared with GemHCl in PDX mice bearing Black and White PCa tumors.Conclusion 4NSG-SLN significantly improved the Gem's pharmacokinetic profile, enhanced Gem's systemic stability increased its antitumor efficacy in PCa PDX mice bearing Black and White patient tumors.

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Combination of anlotinib and gemcitabine promotes the G0/G1 cell cycle arrest and apoptosis of intrahepatic cholangiocarcinoma in vitro

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 17 publications

References 24 publications

Synergistic effects of anlotinib and DDP synergy in breast cancer treatment: inhibiting of cell growth and migration, and augmenting apoptosis and autophagy via modulation of the VEGF/JAK2/STAT3 axis

Synergistic effects of anlotinib and DDP synergy in breast cancer treatment: inhibiting of cell growth and migration, and augmenting apoptosis and autophagy via modulation of the VEGF/JAK2/STAT3 axis

Liensinine inhibits progression of intrahepatic cholangiocarcinoma by regulating TGF‐β1 /P‐smad3 signaling through HIF‐1a

Biological evaluation of novel gemcitabine analog in patient-derived xenograft models of pancreatic cancer

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