bims-nurfca 2024-09-01 papers

Issue of 2024–09–01
four papers selected by
Caner Geyik, Istinye University

Toxicol In Vitro. 2024 Aug 22. pii: S0887-2333(24)00151-6. [Epub ahead of print]101 105921

Silencing Nrf2 in cisplatin resistant non-small cell lung cancer cells augments sensitivity towards EGFR inhibitor.

Chandrani Fouzder, Alpana Mukhuty, Dipanjan Chattopadhyay, Snehasis Das, Sumit Kumar Hira, Rakesh Kundu.

Recently, non-small cell lung cancer (NSCLC) has been the prime concern of cancer clinicians due to its high mortality rate worldwide. Cisplatin, a platinum derivative, has been used as a therapeutic option for treating metastatic NSCLC for several years. However, acquired, or intrinsic drug resistance to Cisplatin is the major obstacle to the successful treatment outcome of patients. Dysregulation of Nrf2 (nuclear factor erythroid 2-related factor 2) and EGFR (epidermal growth factor receptor) signaling have been associated with cellular proliferation, cancer initiation, progression and confer drug resistance to several therapeutic agents including Cisplatin in various cancers. To dissect the molecular mechanism of EGFR activation in resistant cells, we developed Cisplatin-resistant (CisR) human NSCLC cell lines (A549 and NCIH460) with increasing doses of Cisplatin treatment over a 3-month period. CisR cells demonstrated increased proliferative capacity, clonogenic survivability and drug efflux activity compared to the untreated parental (PT) cells. These resistant cells also showed higher levels of Nrf2 and EGFR expression. Here, we found that Nrf2 upregulates both basal and inducible expression of EGFR in these CisR cells at the transcriptional level. Moreover, genetic inhibition of Nrf2 with siRNA in CisR cells showed increased sensitivity towards the EGFR tyrosine kinase inhibitor (TKIs), AG1478. Our study, therefore suggests the use of Nrf2 inhibitors in combinatorial therapy with EGFR TKIs for the treatment of resistant NSCLC.

Keywords: Cisplatin resistance; EGFR; EGFR inhibitor; Lung cancer; NSCLC; Nrf2

DOI: https://doi.org/10.1016/j.tiv.2024.105921

Mar Drugs. 2024 Aug 06. pii: 357. [Epub ahead of print]22(8):

Identification of Penexanthone A as a Novel Chemosensitizer to Induce Ferroptosis by Targeting Nrf2 in Human Colorectal Cancer Cells.

Genshi Zhao, Yanying Liu, Xia Wei, Chunxia Yang, Junfei Lu, Shihuan Yan, Xiaolin Ma, Xue Cheng, Zhengliang You, Yue Ding, Hongwei Guo, Zhiheng Su, Shangping Xing, Dan Zhu.

Ferroptosis has emerged as a potential mechanism for enhancing the efficacy of chemotherapy in cancer treatment. By suppressing nuclear factor erythroid 2-related factor 2 (Nrf2), cancer cells may lose their ability to counteract the oxidative stress induced by chemotherapy, thereby becoming more susceptible to ferroptosis. In this study, we investigate the potential of penexanthone A (PXA), a xanthone dimer component derived from the endophytic fungus Diaporthe goulteri, obtained from mangrove plant Acanthus ilicifolius, to enhance the therapeutic effect of cisplatin (CDDP) on colorectal cancer (CRC) by inhibiting Nrf2. The present study reported that PXA significantly improved the ability of CDDP to inhibit the activity of and induce apoptosis in CRC cells. Moreover, PXA was found to increase the level of oxidative stress and DNA damage caused by CDDP. In addition, the overexpression of Nrf2 reversed the DNA damage and ferroptosis induced by the combination of PXA and CDDP. In vivo experiments using zebrafish xenograft models demonstrated that PXA enhanced the therapeutic effect of CDDP on CRC. These studies suggest that PXA enhanced the sensitivity of CRC to CDDP and induce ferroptosis by targeting Nrf2 inhibition, indicating that PXA might serve as a novel anticancer drug in combination chemotherapy.

Keywords: Nrf2; cisplatin; colorectal cancer; ferroptosis; penexanthone A

DOI: https://doi.org/10.3390/md22080357

Future Med Chem. 2024 ;16(14): 1379-1393

In vitro cytotoxicity screening of some 3-substituted-4-oxo-imidazolidin-2-(1H)-thione derivatives as anticancer drug.

Ibrahim Mohey El-Deen, Elsayed H Eltamany, Nourhan M Ali.

Aim: This study aimed to investigate the in vitro antitumor activity of new series of 2-thiohydanotin derivatives (7 and 9) against two cancer cell lines.Materials & methods: A new series of 2-thioxoimidazolidine derivatives (3-9) were synthesized and investigated for its structure through spectral analysis and also tested against (HepG-2) and (HCT-116) cell line.Results: Among the synthesized compounds, compound 7 halted liver cancer cells at the G0/G1 phase and triggered apoptosis of liver cancer. Contrarily, compound 9 caused colon cancer cells to be arrested at the S phase and trigger apoptosis. Also, they had a good inhibitory effect on (Nrf2).Conclusion: Both compounds had attractive lead molecules for the creation of colon and liver cancer medications.

Keywords: 2-thioxoimidazolidine derivatives; NF-E2-related factor; Nrf2; antiproliferation; cell cycle arrest; colon cancer; liver cancer; quantitative real time PCR

DOI: https://doi.org/10.1080/17568919.2024.2350925

J Control Release. 2024 Aug 28. pii: S0168-3659(24)00585-6. [Epub ahead of print]374 489-504

Harnessing transcription factor-driven ROS for synergistic multimodal lung cancer treatment.

Ye Zhou, Simeng Wang, Jiahua Guo, Chenghao Li, Mengjun Sui, Zekun Zeng, Hui Dang, Qingqing Gu, Jian Zhu, Yangyang Cheng, Peng Hou.

Multimodal treatment of cancer is an unstoppable revolution in clinical application. However, designing a platform that integrates therapeutic modalities with different pharmacokinetic characteristics remains a great challenge. Herein, we designed a universal lipid nanoplatform equipping a ROS-cleavable docetaxel prodrug (DTX-L-DTX) and an NF-E2-related factor 2 (NRF2) inhibitor (clobetasol propionate, CP). This simply fabricated nanomedicine enables superior synergistic molecularly targeted/chemo/radio therapy for lung cancer cascade by a transcription factor-driven ROS self-sustainable motion. Chemotherapy is launched via ROS-triggered DTX release. Subsequently, CP inhibits the expression of NRF2 target genes, resulting in efficient targeted therapy, meanwhile inducing sustained ROS generation which in turn facilitates chemotherapy by overcoming ROS consumption during the DTX release process. Finally, the introduction of radiotherapy further amplifies ROS, offering continuous mutual feedback to amplify the ultimate treatment performance. This strategy is conceptually and operationally simple, providing solutions to challenges in clinical cancer treatment and beyond.

Keywords: Drug delivery; Multimodal cancer therapy; NRF2-targeted; ROS-responsive; Self-sustainable strategy

DOI: https://doi.org/10.1016/j.jconrel.2024.08.035