bims-nurfca 2024-01-14 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024–01–14
thirteen papers selected by
Caner Geyik, Istinye University

Nrf2, A Target for Precision Oncology in Cancer Prognosis and Treatment.
NRF2 activation in BON‑1 neuroendocrine cancer cells reduces the cytotoxic effects of a novel Ruthenium(II)‑curcumin compound: A pilot study.
Oncogenic KEAP1 mutations activate TRAF2-NFκB signaling to prevent apoptosis in lung cancer cells.
Role of SLC7A11/xCT in Ovarian Cancer.
Breast cancer cells have an increased ferroptosis risk induced by system xc- blockade after deliberately downregulating CYTL1 to mediate malignancy.
Formononetin ameliorates cisplatin-induced hair cell death via activation of the PI3K/AKT-Nrf2 signaling pathway.
EGCG-induced selective death of cancer cells through autophagy-dependent regulation of the p62-mediated antioxidant survival pathway.
Quercetin induces ferroptosis in gastric cancer cells by targeting SLC1A5 and regulating the p-Camk2/p-DRP1 and NRF2/GPX4 Axes.
Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice.
A DNA/Upconversion Nanoparticle Complex Enables Controlled Co-Delivery of CRISPR-Cas9 and Photodynamic Agents for Synergistic Cancer Therapy.
A review on the role of FOXD2-AS1 in human disorders.
Dual role of Nrf2/HO-1 pathway in Z-ligustilide-induced ferroptosis against AML cells.
Identification of non-actionable mutations with prognostic and predictive value in patients with advanced or metastatic non-small cell lung cancer.

J Cancer Prev. 2023 Dec 30. 28(4): 131-142

Nrf2, A Target for Precision Oncology in Cancer Prognosis and Treatment.

Hoang Kieu Chi Ngo, Hoang Le, Young-Joon Surh.

  Activating nuclear factor-erythroid 2-related factor (Nrf2), a master regulator of redox homeostasis, has been shown to suppress initiation of carcinogenesis in normal cells. However, this transcription factor has recently been reported to promote proliferation of some transformed or cancerous cells. In tumor cells, Nrf2 is prone to mutations that result in stabilization and concurrent accumulation of its protein product. A hyperactivated mutant form of Nrf2 could support the cancer cells for enhanced proliferation, invasiveness, and resistance to chemotherapeutic agents and radiotherapy, which are associated with a poor clinical outcome. Hence understanding mutations in Nrf2 would have a significant impact on the prognosis and treatment of cancer in the era of precision medicine. This perspective would provide an insight into the genetic alterations in Nrf2 and suggest the application of small molecules, RNAi, and genome editing technologies, particularly CRISR-Cas9, in therapeutic intervention of cancer in the context of the involvement of Nrf2 mutations.

Keywords:  Gene therapy; Mutation; Precision medicine

DOI:  https://doi.org/10.15430/JCP.2023.28.4.131
Oncol Rep. 2024 Feb;pii: 36. [Epub ahead of print]51(2):

NRF2 activation in BON‑1 neuroendocrine cancer cells reduces the cytotoxic effects of a novel Ruthenium(II)‑curcumin compound: A pilot study.

Alessia Garufi, Riccardo Pettinari, Laura Monteonofrio, Giulia Puliani, Ilaria Virdia, Marialuisa Appetecchia, Fabio Marchetti, Mara Cirone, Silvia Soddu, Gabriella D'Orazi.

  Gastroenteropancreatic neuroendocrine neoplasms (GEP‑NEN) are a group of rare tumors whose specific pathogenetic mechanisms of resistance to therapies have not been completely revealed yet. Chemotherapy is the main therapeutic approach in patients with GEP‑NEN, however, novel combination regimens and targeted therapy are continuously explored. In the present study, the anticancer effect of a novel Ruthenium (Ru)(II)‑Bisdemethoxycurcumin (Ru‑bdcurc) compound was evaluated in BON‑1 cell line, one of the few cell lines derived from GEP‑NEN, largely used in experimental research of this type of tumors. The experimental data revealed that the Ru‑bdcurc compound induced cell death in a dose‑dependent manner, in vitro. Biochemical studies demonstrated that, in response to the lower dose of treatment, BON‑1 cells activated the nuclear factor erythroid 2‑related factor 2 (NRF2) pathway with induction of some of its targets including catalase and p62 as well as of the antiapoptotic marker Bcl2, all acting as chemoresistance mechanisms. NRF2 induction associated also with increased expression of endogenous p53 which is reported to be dysfunctional in BON‑1 cells and to inhibit apoptosis. Genetic or pharmacologic targeting of NRF2 inhibited the activation of the NRF2 pathway, as well as of endogenous dysfunctional p53, in response to the lower dose of Ru‑bdcurc, increasing the cell death. To assess the interplay between NRF2 and dysfunctional p53, genetic targeting of p53 showed reduced activation of the NRF2 pathway in response to the lower dose of Ru‑bdcurc, increasing the cell death. These findings identified for the first time a possible dysfunctional p53/NRF2 interplay in BON‑1 cell line that can be a novel key determinant in cell resistance to cytotoxic agents to be evaluated also in GEP‑NEN.

Keywords:  BON‑1 cells; apoptosis; brusatol; chemoresistance; gastroenteropancreatic neuroendocrine tumors; nuclear factor erythroid 2‑related factor 2; p53; ruthenium‑curcumin compounds

DOI:  https://doi.org/10.3892/or.2024.8695
Redox Biol. 2024 Jan 04. pii: S2213-2317(24)00007-7. [Epub ahead of print]69 103031

Oncogenic KEAP1 mutations activate TRAF2-NFκB signaling to prevent apoptosis in lung cancer cells.

Ashik Jawahar Deen, Simone Adinolfi, Jouni Härkönen, Tommi Patinen, Xiaonan Liu, Tuomo Laitinen, Piia Takabe, Kirsi Kainulainen, Sanna Pasonen-Seppänen, Lisa M Gawriyski, Uma Thanigai Arasu, Ilakya Selvarajan, Petri Mäkinen, Hanna Laitinen, Emilia Kansanen, Minna U Kaikkonen, Antti Poso, Markku Varjosalo, Anna-Liisa Levonen.

  The Kelch-like ECH-associated protein 1 (KEAP1) - Nuclear factor erythroid 2 -related factor 2 (NRF2) pathway is the major transcriptional stress response system in cells against oxidative and electrophilic stress. NRF2 is frequently constitutively active in many cancers, rendering the cells resistant to chemo- and radiotherapy. Loss-of-function (LOF) mutations in the repressor protein KEAP1 are common in non-small cell lung cancer, particularly adenocarcinoma. While the mutations can occur throughout the gene, they are enriched in certain areas, indicating that these may have unique functional importance. In this study, we show that in the GSEA analysis of TCGA lung adenocarcinoma RNA-seq data, the KEAP1 mutations in R320 and R470 were associated with enhanced Tumor Necrosis Factor alpha (TNFα) - Nuclear Factor kappa subunit B (NFκB) signaling as well as MYC and MTORC1 pathways. To address the functional role of these hotspot mutations, affinity purification and mass spectrometry (AP-MS) analysis of wild type (wt) KEAP1 and its mutation forms, R320Q and R470C were employed to interrogate differences in the protein interactome. We identified TNF receptor associated factor 2 (TRAF2) as a putative protein interaction partner. Both mutant KEAP1 forms showed increased interaction with TRAF2 and other anti-apoptotic proteins, suggesting that apoptosis signalling could be affected by the protein interactions. A549 lung adenocarcinoma cells overexpressing mutant KEAP1 showed high TRAF2-mediated NFκB activity and increased protection against apoptosis, XIAP being one of the key proteins involved in anti-apoptotic signalling. To conclude, KEAP1 R320Q and R470C and its interaction with TRAF2 leads to activation of NFκB pathway, thereby protecting against apoptosis.

Keywords:  Apoptosis; KEAP1; Lung cancer; NFκB; TNFα; TRAF2

DOI:  https://doi.org/10.1016/j.redox.2024.103031
Int J Mol Sci. 2024 Jan 02. pii: 587. [Epub ahead of print]25(1):

Role of SLC7A11/xCT in Ovarian Cancer.

Sonia Fantone, Federica Piani, Fabiola Olivieri, Maria Rita Rippo, Angelo Sirico, Nicoletta Di Simone, Daniela Marzioni, Giovanni Tossetta.

  Ovarian cancer is one of the most dangerous gynecologic cancers worldwide and has a high fatality rate due to diagnosis at an advanced stage of the disease as well as a high recurrence rate due to the occurrence of chemotherapy resistance. In fact, chemoresistance weakens the therapeutic effects, worsening the outcome of this pathology. Solute Carrier Family 7 Member 11 (SLC7A11, also known as xCT) is the functional subunit of the Xc- system, an anionic L-cystine/L-glutamate antiporter expressed on the cell surface. SLC7A11 expression is significantly upregulated in several types of cancers in which it can inhibit ferroptosis and favor cancer cell proliferation, invasion and chemoresistance. SLC7A11 expression is also increased in ovarian cancer tissues, suggesting a possible role of this protein as a therapeutic target. In this review, we provide an overview of the current literature regarding the role of SLC7A11 in ovarian cancer to provide new insights on SLC7A11 modulation and evaluate the potential role of SLC7A11 as a therapeutic target.

Keywords:  SLC7A11; chemoresistance; compounds; non-coding RNAs; nuclear factor erythroid 2-related factor 2 (NRF2); ovarian cancer; oxidative stress; p53; reactive oxygen species (ROS); xCT

DOI:  https://doi.org/10.3390/ijms25010587
Redox Biol. 2024 Jan 06. pii: S2213-2317(24)00010-7. [Epub ahead of print]70 103034

Breast cancer cells have an increased ferroptosis risk induced by system xc- blockade after deliberately downregulating CYTL1 to mediate malignancy.

Wenwen Xue, Ying Yu, Yongzhong Yao, Lin Zhou, Ying Huang, Yixuan Wang, Zhixiu Chen, Liwei Wang, Xinran Li, Xiaoning Wang, Ronghui Du, Yan Shen, Qiang Xu.

  Cytokine-like protein 1 (CYTL1) expression is deliberately downregulated during the progression of multiple types of cancers, especially breast cancer. However, the metabolic characteristics of cancer progression remain unclear. Here, we uncovered a risk of breast cancer cells harboring low CYTL1 expression, which is metabolically controlled during malignant progression. We performed metabolism comparison and revealed that breast cancer cells with low CYTL1 expression have highly suppressed transsulfuration activity that is driven by cystathionine β-synthase (CBS) and contributes to de novo cysteine synthesis. Mechanistically, CYTL1 activated Nrf2 by promoting autophagic Keap1 degradation, and Nrf2 subsequently transactivated CBS expression. Due to the lack of cellular cysteine synthesis, breast cancer cells with low CYTL1 expression showed hypersensitivity to system xc- blockade-induced ferroptosis in vitro and in vivo. Silencing CBS counteracted CYTL1-mediated ferroptosis resistance. Our results show the importance of exogeneous cysteine in breast cancer cells with low CYTL1 expression and highlight a potential metabolic vulnerability to target.

Keywords:  Breast cancer; CBS; CYTL1; Ferroptosis; Transsulfuration pathway

DOI:  https://doi.org/10.1016/j.redox.2024.103034
Heliyon. 2024 Jan 15. 10(1): e23750

Formononetin ameliorates cisplatin-induced hair cell death via activation of the PI3K/AKT-Nrf2 signaling pathway.

Yimeng Li, Jingfang Wu, Huiqian Yu, Xiaoling Lu, Yusu Ni.

  Cisplatin (CDDP) stands as a highly effective chemotherapeutic agent; however, its ototoxicity remains a perplexing challenge in the field. Formononetin (FMNT), a potent flavonoid isolated from Astragalus membranaceus, displays a diverse range of promising pharmacological activities, encompassing antioxidant, anti-apoptotic, and anti-inflammatory effects. Nonetheless, the advantageous effects of FMNT on cisplatin-induced cochlear hair cell injury demand further investigation. This study aimed to assess the protective properties of FMNT against cisplatin-induced hair cell damage by conducting in vitro assays on explant-cultured cochlear hair cells. The findings revealed that FMNT exhibited a notable reduction in cisplatin-induced hair cell apoptosis. Also, FMNT effectively mitigated the accumulation of reactive oxygen species and mitochondrial damage in cochlear explants exposed to cisplatin, while also restoring the turnover of the reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio. Furthermore, our study demonstrated that FMNT protects hair cells against CDDP injury through the activation of the PI3K/AKT-Nrf2 signaling pathway. Consequently, formononetin emerges as a potential therapeutic agent for the treatment of cisplatin-induced ototoxicity.

Keywords:  Cisplatin; Formononetin; Hair cell; Nuclear factor erythroid 2-related factor 2 (Nrf2); Ototoxicity; Phosphatidylinositol-3-kinase (PI3K)/ serine/threonine kinase 1 (AKT); Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.heliyon.2023.e23750
Biochim Biophys Acta Mol Cell Res. 2024 Jan 10. pii: S0167-4889(24)00002-8. [Epub ahead of print] 119659

EGCG-induced selective death of cancer cells through autophagy-dependent regulation of the p62-mediated antioxidant survival pathway.

Ho Woon Lee, Jee-Hye Choi, Dongbeom Seo, Lkhagvasuren Gavaachimed, Jaesung Choi, Sehwan Park, Na Young Min, Dong Ho Lee, Hyo-Weon Bang, Seung Wook Ham, Jung-Woong Kim, Sung Chul Lee, Sangmyung Rhee, Sang-Beom Seo, Kwang-Ho Lee.

  The effects of EGCG on the selective death of cancer cells by modulating antioxidant pathways through autophagy were explored in various normal and cancer cells. EGCG positively regulated the p62-KEAP1-NRF2-HO-1 pathway in normal cells, while negatively regulating it in cancer cells, leading to selective apoptotic death of cancer cells. In EGCG-treated MRC5 cells (EGCG-MRC5), autophagic flux was blocked, which was accompanied by the formation of p62-positive aggregates. However, EGCG-treated HeLa cells (EGCG-HeLa) showed incomplete autophagic flux and no aggregate formation. The levels of P-ULK1 S556 and S758 increased in EGCG-MRC5 through AMPK-mTOR cooperative interaction. In contrast, EGCG treatment in HeLa cells led to AMPK-induced mTOR inactivation, resulting in abrogation of P-ULK1 S556 and S758 levels. AMPK knockout in EGCG-HeLa restored positive regulation of the p62-mediated pathway, which was accompanied by increased P-mTOR S2448 and P-ULK1 S758 levels. Knockdown of 67LR in EGCG-HeLa abolished AMPK activity but did not restore the p62-mediated pathway. Surprisingly, both AMPK knockout and 67LR knockdown in EGCG-HeLa markedly increased cell viability, despite differential regulation of the antioxidant enzyme HO-1. In conclusion, EGCG induces the selective death of cancer cells through the modulation of at least two autophagy-dependent and independent regulatory pathways: negative regulation involves the mTOR-ULK1 (S556 and S758)-p62-KEAP1-NRF2-HO-1 axis via AMPK activation, whereas positive regulation occurs through the 67LR-AMPK axis.

Keywords:  (−)-Epigallocatechin-3-gallate (EGCG); AKT; AMPK; Autophagy; ROS; p62

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119659
Free Radic Biol Med. 2024 Jan 06. pii: S0891-5849(24)00002-9. [Epub ahead of print]

Quercetin induces ferroptosis in gastric cancer cells by targeting SLC1A5 and regulating the p-Camk2/p-DRP1 and NRF2/GPX4 Axes.

Lixian Ding, Shuwei Dang, Mingjun Sun, Dazhi Zhou, Yanyan Sun, Encheng Li, Shuqi Peng, Jinxing Li, Guodong Li.

  Quercetin (Quer) is a natural flavonoid known for its inhibitory effects against various cancers. However, the mechanism by which Quer inhibits gastric cancer (GC) has not yet been fully elucidated. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abnormalities in the antioxidant system and iron metabolism. Through flow cytometry and other detection methods, we found that Quer elevated lipid peroxidation levels in GC cells. Transmission electron microscopy confirmed an increase in ferroptosis in Quer-induced GC. We demonstrated that Quer inhibits SLC1A5 expression. Molecular docking revealed Quer's binding to SLC1A5 at SER-343, SER-345, ILE-423, and THR-460 residues. Using immunofluorescence and other experiments, we found that Quer altered the intracellular ROS levels, antioxidant system protein expression levels, and iron content. Mechanistically, Quer binds to SLC1A5, inhibiting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), resulting in decreased xCT/GPX4 expression. Quer/SLC1A5 signaling activated p-Camk2, leading to upregulated p-DRP1 and enhanced ROS release. Additionally, Quer increased the intracellular iron content by inhibiting SLC1A5. These three changes collectively led to ferroptosis in GC cells. In conclusion, Quer targets SLC1A5 in GC cells, inhibiting the NRF2/xCT pathway, activating the p-Camk2/p-DRP1 pathway, and accelerating iron deposition. Ultimately, Quer promotes ferroptosis in GC cells, inhibiting GC progression. Overall, our study reveals that Quer can potentially impede GC progression by targeting SLC1A5, offering novel therapeutic avenues through the modulation of ferroptosis and iron homeostasis.

Keywords:  Ferroptosis; Gastric cancer; NRF2; Quercetin; SLC1A5; p-DRP1

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.002
Sci Rep. 2024 01 09. 14(1): 924

Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice.

Hu Tuo, Wenjing Li, Wei Zhao, Juan Zhao, Danni Li, Lin Jin.

Doxorubicin (DOX) is a popular and potent anticancer drug, but its cardiotoxicity limits its clinical application. Shikonin has a wide range of biological functions, including antioxidant and anti-inflammatory effects. The aim of this study was to investigate the effects of shikonin on DOX-induced cardiac injury and to identify the underlying mechanisms. Mice receiving shikonin showed reduced cardiac injury response and enhanced cardiac function after DOX administration. Shikonin significantly attenuated DOX-induced oxidative damage, inflammation accumulation and cardiomyocyte apoptosis. Shikonin protects against DOX-induced cardiac injury by inhibiting Mammalian sterile 20-like kinase 1 (Mst1) and oxidative stress and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In conclusion, shikonin alleviates DOX-induced cardiotoxicity by inhibiting Mst1 and activating Nrf2. Shikonin may be used to treat DOX-induced cardiac injury.

DOI: https://doi.org/10.1038/s41598-024-51675-7
Adv Mater. 2024 Jan 10. e2309534

A DNA/Upconversion Nanoparticle Complex Enables Controlled Co-Delivery of CRISPR-Cas9 and Photodynamic Agents for Synergistic Cancer Therapy.

Nachuan Song, Xiaoting Fan, Xiaocui Guo, Jianpu Tang, Hongjin Li, Ruoyu Tao, Fengqin Li, Junru Li, Dayong Yang, Chi Yao, Peifeng Liu.

  Photodynamic therapy (PDT) is a noninvasive therapeutic strategy that depends on the light-irradiated exciting of photosensitizer (PS) to generate reactive oxygen species (ROS), which faces challenges and limitations in hypoxia and antioxidant response of cancer cells, and limited tissue-penetration of light. Herein, we develop a multi-functional DNA/upconversion nanoparticles (UCNPs) complex that enables controlled co-delivery of CRISPR-Cas9, hemin, and protoporphyrin (PP) for synergistic PDT activated by near-infrared (NIR) light. An ultra-long ssDNA is prepared via rolling circle amplification (RCA), which contains recognition sequences of sgRNA for loading Cas9 ribonucleoprotein (RNP), G-quadruplex sequences for loading hemin and PP, and linker sequences for combining UCNP. Cas9 RNP precisely cleaves the antioxidant regulator nuclear factor E2-related factor 2 (Nrf2) gene, improving the sensitivity of cancer cells to ROS, and enhancing the synergistic PDT effect. The G-quadruplex/hemin DNAzyme mimicks horseradish peroxidase (HRP) to catalyze the endogenous H2 O2 to O2 , overcoming the hypoxia condition in tumors. The introduced UCNP converts NIR irradiation with deep tissue penetration to light with shorter wavelength, exciting PP to transform the abundant O2 to 1 O2 . The integration of gene editing and PDT allows substantial accumulation of 1 O2 in cancer cells for enhanced cell apoptosis, and this synergistic PDT has shown remarkable therapeutic efficacy in a breast cancer mouse model. This article is protected by copyright. All rights reserved.

Keywords:  CRISPR-Cas9; DNA Nanotechnology; Gene Editing; Photodynamic Therapy; Upconversion Nanoparticle

DOI:  https://doi.org/10.1002/adma.202309534
Pathol Res Pract. 2024 Jan 09. pii: S0344-0338(24)00012-8. [Epub ahead of print]254 155101

A review on the role of FOXD2-AS1 in human disorders.

Soudeh Ghafouri-Fard, Atefeh Harsij, Bashdar Mahmud Hussen, Hasan Pourmoshtagh, Mohammad Taheri.

  FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) is a long non-coding RNA being transcribed from a locus on chromosome 1p33. This transcript has been found to be up-regulated in tumor samples of almost all types of malignancies in association with a significant increase in malignant features. FOXD2-AS1 can affect activity of PI3K/AKT, AKT/mTOR, Hippo/YAP, Notch, NRf2, Wnt/β-catenin, NF-ƙB and ERK/MAPK pathways. Furthermore, it can enhance stem cell properties in cancer cells and prompt epithelial-mesenchymal transition. It is also involved in induction of resistance to a variety of anticancer agents such as adriamycin, cisplatin, 5-fluorouracil, temozolomide and gemcitabine. This article summarizes the impact of FOXD2-AS1 in diverse human disorders.

Keywords:  Cancer; FOXD2-AS1; LncRNA

DOI:  https://doi.org/10.1016/j.prp.2024.155101
Phytomedicine. 2023 Dec 16. pii: S0944-7113(23)00646-3. [Epub ahead of print]124 155288

Dual role of Nrf2/HO-1 pathway in Z-ligustilide-induced ferroptosis against AML cells.

Zhigang Chen, Qiang Zhu, Xingyu Qi, Li-Rong Yang, Yu-Xia Rong, Qi Wei, Shi-Qi Wu, Qian-Wei Lu, Li Li, Ming-Dong Jiang, Hongyi Qi.

   BACKGROUND: The scarcity of drugs targeting AML cells poses a significant challenge in AML management. Z-Ligustilide (Z-LIG), a phthalide compound, shows promising pharmacological potential as a candidate for AML therapy. However, its precise selective mechanism remains unclear.
PURPOSE: In order to assess the selective inducement effects of Z-LIG on ferroptosis in AML cells and explore the possible involvement of the Nrf2/HO-1 pathway in the regulation of ferroptosis.
METHODS: Through in vitro cell proliferation and in vivo tumor growth tests, the evaluation of Z-LIG's anticancer activity was conducted. Ferroptosis was determined by the measurement of ROS and lipid peroxide levels using flow cytometry, as well as the observation of mitochondrial morphology. To analyze the iron-related factors, western blot analysis was employed. The up-regulation of the Nrf2/HO-1 axis was confirmed through various experimental techniques, including CRISPR/Cas9 gene knockout, fluorescent probe staining, and flow cytometry. The efficacy of Z-LIG in inducing ferroptosis was further validated in a xenograft nude mouse model.
RESULTS: Our study revealed that Z-LIG specifically triggered lipid peroxidation-driven cell death in AML cells. Z-LIG downregulated the total protein and nuclear entrance levels of IRP2, resulting in upregulation of FTH1 and downregulation of TFR1. Z-LIG significantly increased the susceptibility to ferroptosis by upregulating ACSL4 levels and simultaneously suppressing the activity of GPX4. Notably, the Nrf2/HO-1 pathway displayed a twofold impact in the ferroptosis induced by Z-LIG. Mild activation suppressed ferroptosis, while excessive activation promoted it, mainly driven by ROS-induced labile iron pool (LIP) accumulation in AML cells, which was not observed in normal human cells. Additionally, Nrf2 knockout and HO-1 knockdown reversed iron imbalance and mitochondrial damage induced by Z-LIG in HL-60 cells. Z-LIG effectively inhibited the growth of AML xenografts in mice, and Nrf2 knockout partially weakened its antitumor effect by inhibiting ferroptosis.
CONCLUSION: Our study presents biological proof indicating that the selective initiation of ferroptosis in leukemia cells is credited to the excessive activation of the Nrf2/HO-1 pathway triggered by Z-LIG.

Keywords:  Acute myeloid leukemia; Ferroptosis; Nrf2/HO-1; Z-ligustilide

DOI:  https://doi.org/10.1016/j.phymed.2023.155288
Clin Transl Oncol. 2024 Jan 06.

Identification of non-actionable mutations with prognostic and predictive value in patients with advanced or metastatic non-small cell lung cancer.

Mariano Provencio-Pulla, Diego Pérez-Parente, Sara Olson, Haroon Hasan, Begoña Campos Balea, Delvys Rodríguez-Abreu, Marta López-Brea Piqueras, Navdeep Pal, Samantha Wilkinson, Esther Vilas, Pedro Ruiz-Gracia, Manuel Cobo-Dols.

   INTRODUCTION: Lung cancer is one of the most prevalent cancers and the leading cause of cancer death. Advanced non-small cell lung cancer (aNSCLC) patients frequently harbor mutations that impact their survival outcomes. There are limited data regarding the prognostic and predictive significance of these mutations on survival outcomes in the real-world setting.
METHODS: This observational retrospective study analyzed de-identified electronic medical records from the Flatiron Health Clinico-Genomic and FoundationCore® databases to identify patients with aNSCLC who initiated first-line immune checkpoint inhibitors (ICI; alone or in combination) or chemotherapy under routine care between 2016 and 2021. The primary objectives were to assess the prevalence of non-actionable mutations and to determine their association with overall survival (OS). Real-world progression-free survival (rwPFS) and real-world response (rwR) were investigated as secondary exploratory outcomes.
RESULTS: Based on an assessment of 185 non-actionable mutations in 2999 patients, the most prevalent mutations were TP53 (70%), KRAS (42%), CDKN2A/B (31%), and STK11 (21%). STK11, KEAP1, and CDKN2A/B mutations were significantly associated with lower rwR, shorter rwPFS and OS. KRAS mutations were clinically associated with shorter rwPFS in CIT-treated patients. Subgroup analysis revealed that fast progressors were significantly more likely to harbor STK11, KEAP1, and CDKN2A/B mutations. Accordingly, long-term survivors (LTS) showed a significantly lower prevalence of these mutations.
CONCLUSION: Our results provide evidence on the prognostic value of STK11, KEAP1, and CDKN2A/B mutations in patients with aNSCLC. Further research is required to better understand the implications of these findings on patient management and future trial design and treatment selection.

Keywords:  NSCLC; Non-actionable mutations; Prognosis; Real-world; Survival

DOI:  https://doi.org/10.1007/s12094-023-03362-8