Apigenin inhibits the inducible expression of programmed death ligand 1 by human and mouse mammary carcinoma cells

Coombs, Melanie R. Power; Harrison, Megan; Hoskin, David W.

doi:10.1016/j.canlet.2016.06.023

Cited by 94 publications

(66 citation statements)

References 43 publications

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“…A previous study in our group showed that flavonoid CH625 increased survival and decreased tumor burden with enhanced antitumor immunity in C6 and GL261gliomas . In addition, a recent study from another group has shown that flavone apigenin inhibits PD-L1 expression and enhances T-cell proliferation in breast cancer (Coombs et al, 2016). Here we demonstrated that flavonoid Mel improves anti-PD-1 therapy in the LLC and CMT167 models with few side effects.…”

Section: Discussionsupporting

confidence: 65%

“…We previously reported that flavonoid CH625 normalizes vasculature while accompanied by increased antitumor immunity in C6 and GL261gliomas . A recent study from another group demonstrated that flavone apigenin suppresses expression of PD-L1 and enhances proliferation of T cells in breast cancer (Coombs et al, 2016). However, whether the flavonoid improves the anti-PD-1 checkpoint blockade therapy has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer

Tang¹,

Liu²,

Wang³

et al. 2018

J Pharmacol Exp Ther

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Checkpoint blockade therapy has been proven efficacious in lung cancer patients. However, primary/acquired resistance hampers its efficacy. Therefore, there is an urgent need to develop novel strategies to improve checkpoint blockade therapy. Here we tested whether dual inhibition of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) by flavonoid melafolone improves program death 1 (PD-1) checkpoint blockade therapy through normalizing tumor vasculature and PD-1 ligand (PD-L1) downregulation. Virtual screening assay, cellular thermal shift assay, and enzyme inhibition assay identified melafolone as a potential inhibitor of COX-2 and EGFR. In Lewis lung carcinoma (LLC) and CMT167 models, dual inhibition of COX-2 and EGFR by melafolone promoted survival, tumor growth inhibition, and vascular normalization, and ameliorated CD8 1 T-cell suppression, accompanied by the downregulation of transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), and PD-L1 in the tumor cells. Mechanistically, dual inhibition of COX-2 and EGFR in lung cancer cells by melafolone increased the migration of pericyte, decreased the proliferation and migration of endothelial cells, and enhanced the proliferation and effector function of CD8 1 T cells through VEGF, TGF-b, or PD-L1 downregulation and PI3K/AKT inactivation. Notably, melafolone improved PD-1 immunotherapy against LLC and CMT167 tumors. Together, dual inhibition of COX-2 and EGFR by melafolone improves checkpoint blockade therapy through vascular normalization and PD-L1 downregulation and, by affecting vessels and immune cells, may be a promising combination strategy for the treatment of human lung cancer.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer

Tang¹,

Liu²,

Wang³

et al. 2018

J Pharmacol Exp Ther

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“…A sub-cytotoxic concentration of apigenin inhibits IFN-γ-induced PD-L1 expression in MDA-MB-468 and 4T1 breast cancer cells, associated with reduced phosphorylation of STAT1, transiently at Tyr701 and persistently at Ser727. However, apigenin exposure did not affect constitutive PD-L1 expression in triple-negative MDA-MB-231 BC cells but was more susceptible to T-cell-mediated antitumor immune responses [64]. …”

Section: 0 Effect Of Apigenin In Various Human Cancersmentioning

confidence: 99%

Plant Flavone Apigenin: an Emerging Anticancer Agent

et al. 2017

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Research in cancer chemoprevention provides convincing evidence that increased intake of vegetables and fruits may reduce the risk of several human malignancies. Phytochemicals present therein provide beneficial anti-inflammatory and antioxidant properties that serve to improve the cellular microenvironment. Compounds known as flavonoids categorized anthocyanidins, flavonols, flavanones, flavonols, flavones, and isoflavones have shown considerable promise as chemopreventive agents. Apigenin (4′, 5, 7-trihydroxyflavone), a major plant flavone, possessing antioxidant, anti-inflammatory, and anticancer properties affecting several molecular and cellular targets used to treat various human diseases. Epidemiologic and case-control studies have suggested apigenin reduces the risk of certain cancers. Studies demonstrate that apigenin retain potent therapeutic properties alone and/or increases the efficacy of several chemotherapeutic drugs in combination on a variety of human cancers. Apigenin’s anticancer effects could also be due to its differential effects in causing minimal toxicity to normal cells with delayed plasma clearance and slow decomposition in liver increasing the systemic bioavailability in pharmacokinetic studies. Here we discuss the anticancer role of apigenin highlighting its potential activity as a chemopreventive and therapeutic agent. We also highlight the current caveats that preclude apigenin for its use in the human trials.

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“…Programmed death receptor 1 (PD-1) is a crucial immunosuppressive molecule found in CTLs, BC cells, and antigen-presenting cells 31. The interaction between PD-1 and its ligand, PD-L1, on the surface of tumor cells, inhibits the activation of effector T cells, which induce FasL and interleukin (IL) 10.…”

Section: Tumor-related Immune Evasionmentioning

confidence: 99%

Mechanism of immune evasion in breast cancer

Wang¹,

Zhang²,

Song³

et al. 2017

OTT

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Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body’s immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail.

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Apigenin inhibits the inducible expression of programmed death ligand 1 by human and mouse mammary carcinoma cells

Cited by 94 publications

References 43 publications

Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer

Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer

Plant Flavone Apigenin: an Emerging Anticancer Agent

Mechanism of immune evasion in breast cancer

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