Therapeutic potentials of Apatinib in cancer treatment: Possible mechanisms and clinical relevance

Maroufi, Nazila Fathi; Rashidi, Mohammad; Vahedian, Vahid; Akbarzadeh, Maryam; Fattahi, Amir; Nouri, Mohammad

doi:10.1016/j.lfs.2019.117106

Cited by 62 publications

(39 citation statements)

References 69 publications

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“…Apatinib is a novel tyrosine kinase inhibitor (TKI) that approved and launched in China with promising therapeutic efficacy and tolerance in the treatment of multiple solid tumors [9]. Apatinib exerts its antigenic effects by inhibiting VEGFR-induced proliferation and migration of endothelial cells via highly and selectively targeting VEGFR2 [10]. Multiple clinical trials have demonstrated the antitumor activity of apatinib in monotherapy or combination therapy in advanced NSCLC patients [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Xie

Zhou

Liang

et al. 2021

J Exp Clin Cancer Res

114

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Background Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear. Methods MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors. Results We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo. Conclusion Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling.

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Section: Introductionmentioning

confidence: 99%

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Xie

Zhou

Liang

et al. 2021

J Exp Clin Cancer Res

114

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“…17 Tumor cells can influence the TME by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the TME are compromised to the growth and evolution of cancerous cells. Apatinib is a novel tyrosine kinase inhibitor that selectively binds and inhibits VEGFR-2 11 and has shown promising activity in treating ovarian cancer. 18 Recent studies showed that apatinib is a feasible treatment in patients with recurrent, platinumresistant EOC 19 and the synergistic effect of combining antiangiogenesis with immune checkpoint inhibitors.…”

Section: Discussionmentioning

confidence: 99%

αPD-1-mesoCAR-T cells partially inhibit the growth of advanced/refractory ovarian cancer in a patient along with daily apatinib

Fang

Ding

Guo

et al. 2021

J Immunother Cancer

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Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies in China. In particular, advanced/refractory ovarian cancer lacks effective targeted therapies due to the immunosuppressive and proangiogenic tumor microenvironment. Mesothelin (MSLN) has been found to be highly expressive in most EOC. Targeting MSLN by antibodies or chimeric antigen receptor-modified T (CAR-T) cells and immune checkpoint blockades as well as apatinib, an anti-angiogenic drug, have been used in patients with refractory ovarian cancer. Apatinib was reported to promote the infiltration of CD8+ T cells in lung cancer. However, the combination therapy of CAR-T secreting anti-PD-1 antibody with apatinib in EOC has not been reported.Case presentationHere we report a case of refractory EOC in a patient who had relapsed after multiline chemotherapy. The patient received autologous T cells that contained sequences encoding single-chain variable fragments specific for MSLN and full-length antibody for PD-1 (αPD-1). The modified T cells were called αPD-1-mesoCAR-T cells. After infusion, the copy number and PD-1 antibody secretion of the CAR-T cells were increased in the blood. By application of multimodality tumor tracking, MRI of the liver showed shrinkage of metastatic nodules from average diameter of 71.3–39.1 mm at month 2. The patient achieved partial response and survived more than 17 months. IL-6 levels in the patient fluctuated from the baseline to 2–4-folds after treatment, but side effects were mild with only grade 1 hypertension and fatigue.ConclusionαPD-1-mesoCAR-T cell therapy combined with apatinib demonstrates a potential therapeutic effect on advanced refractory ovarian cancer.Trial registration numberNCT03615313.

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“…One of the prerequisites for tumor growth is the generation of internal blood vessels, which can provide sufficient nutrients that provide the material basis for the growth, infiltration, and metastasis of tumor cells ( 28 , 75 ). Therefore, blocking and inhibiting the generation of blood vessels play a vital role in the treatment of malignant tumors.…”

Section: Comparisons Of Anlotinib With Apatinib and Bevacizumabmentioning

confidence: 99%

Anlotinib: A Novel Targeted Drug for Bone and Soft Tissue Sarcoma

2021

Front. Oncol.

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Bone and soft tissue sarcomas account for approximately 15% of pediatric solid malignant tumors and 1% of adult solid malignant tumors. There are over 50 subtypes of sarcomas, each of which is notably heterogeneous and manifested by remarkable phenotypic and morphological variability. Anlotinib is a novel oral tyrosine kinase inhibitor (TKI) targeting c-kit, platelet-derived growth factor receptors, fibroblast growth factor receptor, and vascular endothelial growth factor receptor. In comparison with the placebo, anlotinib was associated with better overall survival and progression-free survival (PFS) in a phase III trial of patients with advanced non-small cell lung cancer (NSCLC), albeit with cancer progression after two previous lines of treatment. Recently, the National Medical Products Administration approved anlotinib monotherapy as a third-line treatment for patients with advanced NSCLC. Additionally, a phase IIB randomized trial substantiated that anlotinib is associated with a significant longer median PFS in patients with advanced soft tissue sarcoma. Moreover, anlotinib is also effective in patients with advanced medullary thyroid carcinoma and metastatic renal cell carcinoma. Anlotinib has similar tolerability to other TKIs targeting vascular endothelial growth factor receptors and other tyrosine kinase-mediated pathways. However, anlotinib has a notably lower rate of side effects ≥grade 3 relative to sunitinib. This review discussed the remarkable characteristics and major dilemmas of anlotinib as a targeted therapy for sarcomas.

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Therapeutic potentials of Apatinib in cancer treatment: Possible mechanisms and clinical relevance

Cited by 62 publications

References 69 publications

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

αPD-1-mesoCAR-T cells partially inhibit the growth of advanced/refractory ovarian cancer in a patient along with daily apatinib

Anlotinib: A Novel Targeted Drug for Bone and Soft Tissue Sarcoma

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