Overcoming therapeutic resistance to platinum-based drugs by targeting Epithelial–Mesenchymal transition

Duan, Xirui; Luo, Maochao; Li, Jian; Shen, Zhisen; Xie, Ke

doi:10.3389/fonc.2022.1008027

Cited by 12 publications

(10 citation statements)

References 177 publications

(53 reference statements)

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“…In the synergistic phototherapy experiment in vivo , the results showed that the tumor volume of the ICG-PtMGs@HGd group under NIR irradiation decreased most significantly, and the body weight of the tumor-bearing mice did not change significantly after treatment. In general, there is a wide range of biological applications of Pt-based nanomaterials, but the toxic side effects caused by heavy metals are still current challenges to be overcome ( Duan et al, 2022 ; Velcheva et al, 2022 ).…”

Section: Nanomaterial-mediated Tumor Hypoxia Reliefmentioning

confidence: 99%

Nanotechnological strategies to increase the oxygen content of the tumor

et al. 2023

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Hypoxia is a negative prognostic indicator of solid tumors, which not only changes the survival state of tumors and increases their invasiveness but also remarkably reduces the sensitivity of tumors to treatments such as radiotherapy, chemotherapy and photodynamic therapy. Thus, developing therapeutic strategies to alleviate tumor hypoxia has recently been considered an extremely valuable target in oncology. In this review, nanotechnological strategies to elevate oxygen levels in tumor therapy in recent years are summarized, including (I) improving the hypoxic tumor microenvironment, (II) oxygen delivery to hypoxic tumors, and (III) oxygen generation in hypoxic tumors. Finally, the challenges and prospects of these nanotechnological strategies for alleviating tumor hypoxia are presented.

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Section: Nanomaterial-mediated Tumor Hypoxia Reliefmentioning

confidence: 99%

Nanotechnological strategies to increase the oxygen content of the tumor

et al. 2023

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“…Chemoresistance remains a major challenge in the management of patients with CRC. Several mechanisms of oxaliplatin resistance have been reported, including reduced cellular drug uptake and accumulation [ 26 ], increased repair of DNA damage [ 27 ], induction of epithelial-mesenchymal transition (EMT) [ 28 ], and desensitization to cell apoptosis [ 29 ]; however, effective strategies for reversing resistance have not been achieved. Emerging evidence suggests that aberrant cancer metabolism could impart drug resistance [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer

Huang,

Chan,

Chen

et al. 2024

J Transl Med

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Background Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC. Methods An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5ʹ-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell apoptosis in vivo and in vitro. Results Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/β-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/β-catenin and IMPDH2. Blocking the Wnt/β-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP. Conclusions IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.

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“…Development of the EMT phenotype is one of the major mechanisms that allow tumor cells to become resistant to platinum-based drug [ 223 ]. Since cisplatin is the first-line option for NPC chemotherapy, exploiting treatment to prevent or reverse EMT is of great importance.…”

Section: Strategies To Overcome Drug Resistance In Npcmentioning

confidence: 99%

Nasopharyngeal carcinoma: current views on the tumor microenvironment's impact on drug resistance and clinical outcomes

Liu,

Tang,

et al. 2024

Mol Cancer

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The incidence of nasopharyngeal carcinoma (NPC) exhibits significant variations across different ethnic groups and geographical regions, with Southeast Asia and North Africa being endemic areas. Of note, Epstein-Barr virus (EBV) infection is closely associated with almost all of the undifferentiated NPC cases. Over the past three decades, radiation therapy and chemotherapy have formed the cornerstone of NPC treatment. However, recent advancements in immunotherapy have introduced a range of promising approaches for managing NPC. In light of these developments, it has become evident that a deeper understanding of the tumor microenvironment (TME) is crucial. The TME serves a dual function, acting as a promoter of tumorigenesis while also orchestrating immunosuppression, thereby facilitating cancer progression and enabling immune evasion. Consequently, a comprehensive comprehension of the TME and its intricate involvement in the initiation, progression, and metastasis of NPC is imperative for the development of effective anticancer drugs. Moreover, given the complexity of TME and the inter-patient heterogeneity, personalized treatment should be designed to maximize therapeutic efficacy and circumvent drug resistance. This review aims to provide an in-depth exploration of the TME within the context of EBV-induced NPC, with a particular emphasis on its pivotal role in regulating intercellular communication and shaping treatment responses. Additionally, the review offers a concise summary of drug resistance mechanisms and potential strategies for their reversal, specifically in relation to chemoradiation therapy, targeted therapy, and immunotherapy. Furthermore, recent advances in clinical trials pertaining to NPC are also discussed.

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Overcoming therapeutic resistance to platinum-based drugs by targeting Epithelial–Mesenchymal transition

Cited by 12 publications

References 177 publications

Nanotechnological strategies to increase the oxygen content of the tumor

Nanotechnological strategies to increase the oxygen content of the tumor

Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer

Nasopharyngeal carcinoma: current views on the tumor microenvironment's impact on drug resistance and clinical outcomes

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