Nrf2 Inhibitor, Brusatol in Combination with Trastuzumab Exerts Synergistic Antitumor Activity in HER2-Positive Cancers by Inhibiting Nrf2/HO-1 and HER2-AKT/ERK1/2 Pathways

Yang, Yun; Tian, Ziyin; Guo, Rui; Ren, Feng

doi:10.1155/2020/9867595

Cited by 38 publications

(40 citation statements)

References 51 publications

(66 reference statements)

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“…Pharmacological inhibition of Nrf2 using trigonelline sensitized pancreatic cells to apoptosis [ 82 ]. Synergistic anti-cancer effects of brusatol and trastuzumab (HER2 targeting agent) were reported in HER2 positive BC and associated with induction of reactive oxygen species (ROS) production and apoptosis [ 83 ]. Furthermore, cooperative effects of brusatol and other anticancer agents, including gemcitabine (in pancreatic carcinomas) [ 84 ], cytarabine (Ara-C) (in acute myeloid leukemia) [ 85 ], luteolin (in gastric cancers) [ 86 ], and paclitaxel (in BCs) [ 87 , 88 ], were observed.…”

Section: Discussionmentioning

confidence: 99%

Targeted Inhibition of Anti-Inflammatory Regulator Nrf2 Results in Breast Cancer Retardation In Vitro and In Vivo

et al. 2021

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Nuclear factor erythroid-2 related factor-2 (Nrf2) is an oxidative stress-response transcriptional activator that promotes carcinogenesis through metabolic reprogramming, tumor promoting inflammation, and therapeutic resistance. However, the extension of Nrf2 expression and its involvement in regulation of breast cancer (BC) responses to chemotherapy remain largely unclear. This study determined the expression of Nrf2 in BC tissues (n = 46) and cell lines (MDA-MB-453, MCF-7, MDA-MB-231, MDA-MB-468) with diverse phenotypes. Immunohistochemical (IHC)analysis indicated lower Nrf2 expression in normal breast tissues, compared to BC samples, although the difference was not found to be significant. However, pharmacological inhibition and siRNA-induced downregulation of Nrf2 were marked by decreased activity of NADPH quinone oxidoreductase 1 (NQO1), a direct target of Nrf2. Silenced or inhibited Nrf2 signaling resulted in reduced BC proliferation and migration, cell cycle arrest, activation of apoptosis, and sensitization of BC cells to cisplatin in vitro. Ehrlich Ascites Carcinoma (EAC) cells demonstrated elevated levels of Nrf2 and were further tested in experimental mouse models in vivo. Intraperitoneal administration of pharmacological Nrf2 inhibitor brusatol slowed tumor cell growth . Brusatol increased lymphocyte trafficking towards engrafted tumor tissue in vivo, suggesting activation of anti-cancer effects in tumor microenvironment. Further large-scale BC testing is needed to confirm Nrf2 marker and therapeutic capacities for chemo sensitization in drug resistant and advanced tumors.

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Section: Discussionmentioning

confidence: 99%

Targeted Inhibition of Anti-Inflammatory Regulator Nrf2 Results in Breast Cancer Retardation In Vitro and In Vivo

et al. 2021

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“…For example, Xiang et al reported that brusatol abrogate gemcitabine-induced NRF2 activation in pancreatic cancer cells and potentiates gemcitabine-induced cell growth inhibition in vitro and xenograft tumor growth inhibition in vivo with reduced NRF2 expression in brusatol-treated xenograft tumors [ 108 ]; Yang, et al reported that brusatol synergistically enhanced the antitumor activity of trastuzumab against HER2-positive cancer cells [ 109 ]; trastuzumab markedly enhanced brusatol-induced ROS accumulation and apoptosis level [ 109 ]. The authors stated that the study is a new insight on exploring NRF2 inhibition in combination with HER2-targeted trastuzumab as a potential clinical treatment regimen for treating HER2-positive cancers [ 109 ]; Very recently, Xie, et al reported that in lung cancer cells, brusatol significantly suppressed the expression of NRF2 and HO-1 (a NRF2 downstream target), and abrogated tBHQ-induced NRF2 activation [ 110 ]; brusatol suppressed the expression level of Bcl-2 and Bcl-xl, accentuated Bax and Bak, increased cleaved caspases-3/8, and cleaved PARP but upregulated XIAP [ 110 ]. These authors proposed that brusatol action may involve the modulation of ROS-mediated mitochondrial-dependent pathway and inhibition of NRF2-mediated antioxidant response [ 110 ].…”

Section: Nrf2mentioning

confidence: 99%

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

Aljahdali

Zhang

et al. 2021

J Exp Clin Cancer Res

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The incidence of renal cell carcinoma (RCC) is increasing worldwide with an approximate 20% mortality rate. The challenge in RCC is the therapy-resistance. Cancer resistance to treatment employs multiple mechanisms due to cancer heterogeneity with multiple genetic and epigenetic alterations. These changes include aberrant overexpression of (1) anticancer cell death proteins (e.g., survivin/BIRC5), (2) DNA repair regulators (e.g., ERCC6) and (3) efflux pump proteins (e.g., ABCG2/BCRP); mutations and/or deregulation of key (4) oncogenes (e.g., MDM2, KRAS) and/or (5) tumor suppressor genes (e.g., TP5/p53); and (6) deregulation of redox-sensitive regulators (e.g., HIF, NRF2). Foci of tumor cells that have these genetic alterations and/or deregulation possess survival advantages and are selected for survival during treatment. We will review the significance of survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, TP5/p53, KRAS and AKT in treatment resistance as the potential therapeutic biomarkers and/or targets in RCC in parallel with our analized RCC-relevant TCGA genetic results from each of these gene/protein molecules. We then present our data to show the anticancer drug FL118 modulation of these protein targets and RCC cell/tumor growth. Finally, we include additional data to show a promising FL118 analogue (FL496) for treating the specialized type 2 papillary RCC.

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“…As a natural quassinoid, brusatol is known to stimulate the polyubiquitination of NRF2 and inhibit NRF2 signaling [ 65 ] ( Figure 1 ). Studies suggest its usage as an antineoplastic drug and chemotherapeutic adjuvant [ 66 , 67 ]. However, brusatol causes various cardiovascular side effects and may lead to serious neurologic and organ damage by reversing the therapeutic effects of other drugs.…”

Section: Nddss In the Delivery Of Nrf2 Modulators For Cancer Therapymentioning

confidence: 99%

Nanotechnology-Based Drug Delivery to Improve the Therapeutic Benefits of NRF2 Modulators in Cancer Therapy

et al. 2021

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The disadvantages of conventional anticancer drugs, such as their low bioavailability, poor targeting efficacy, and serious side effects, have led to the discovery of new therapeutic agents and potential drug delivery systems. In particular, the introduction of nano-sized drug delivery systems (NDDSs) has opened new horizons for effective cancer treatment. These are considered potential systems that provide deep tissue penetration and specific drug targeting. On the other hand, nuclear factor erythroid 2-related factor 2 (NRF2)-based anticancer treatment approaches have attracted tremendous attention and produced encouraging results. However, the lack of effective formulation strategies is one of the factors that hinder the clinical application of NRF2 modulators. In this review, we initially focus on the critical role of NRF2 in cancer cells and NRF2-based anticancer treatment. Subsequently, we review the preparation and characterization of NDDSs encapsulating NRF2 modulators and discuss their potential for cancer therapy.

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Nrf2 Inhibitor, Brusatol in Combination with Trastuzumab Exerts Synergistic Antitumor Activity in HER2-Positive Cancers by Inhibiting Nrf2/HO-1 and HER2-AKT/ERK1/2 Pathways

Cited by 38 publications

References 51 publications

Targeted Inhibition of Anti-Inflammatory Regulator Nrf2 Results in Breast Cancer Retardation In Vitro and In Vivo

Targeted Inhibition of Anti-Inflammatory Regulator Nrf2 Results in Breast Cancer Retardation In Vitro and In Vivo

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

Nanotechnology-Based Drug Delivery to Improve the Therapeutic Benefits of NRF2 Modulators in Cancer Therapy

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