Modulating undruggable targets to overcome cancer therapy resistance

Passirani, Catherine; Vessières, Anne; Regina, Giuseppe La; Link, Wolfgang; Silvestri, Romano

doi:10.1016/j.drup.2021.100788

Cited by 20 publications

(13 citation statements)

References 358 publications

(372 reference statements)

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“…Conventional chemotherapy, radiotherapy and surgery provide effective local control of colon cancer. However, serious side effects and resistance to therapies over time decrease the survival rate of patients [ 4 ]. Despite recent dramatic advances in early diagnosis and treatment, there still remains an unmet need to palliate CRC symptoms, develop novel therapeutic strategies with lower side effects, and prolong the overall survival of the patients [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptome Profiling of HCT-116 Colorectal Cancer Cells with RNA Sequencing Reveals Novel Targets for Polyphenol Nano Curcumin

Azeez

Neri²,

Feizi³

et al. 2022

Molecules

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Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. The gemini nanoparticle formulation of polyphenolic curcumin significantly inhibits the viability of cancer cells. However, the molecular mechanisms and pathways underlying its toxicity in colon cancer are unclear. Here, we aimed to uncover the possible novel targets of gemini curcumin (Gemini-Cur) on colorectal cancer and related cellular pathways. After confirming the cytotoxic effect of Gemini-Cur by MTT and apoptotic assays, RNA sequencing was employed to identify differentially expressed genes (DEGs) in HCT-116 cells. On a total of 3892 DEGs (padj < 0.01), 442 genes showed a log2 FC >|2| (including 244 upregulated and 198 downregulated). Gene ontology (GO) enrichment analysis was performed. Protein–protein interaction (PPI) and gene-pathway networks were constructed by using STRING and Cytoscape. The pathway analysis showed that Gemini-Cur predominantly modulates pathways related to the cell cycle. The gene network analysis revealed five central genes, namely GADD45G, ATF3, BUB1B, CCNA2 and CDK1. Real-time PCR and Western blotting analysis confirmed the significant modulation of these genes in Gemini-Cur-treated compared to non-treated cells. In conclusion, RNA sequencing revealed novel potential targets of curcumin on cancer cells. Further studies are required to elucidate the molecular mechanism of action of Gemini-Cur regarding the modulation of the expression of hub genes.

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Section: Introductionmentioning

confidence: 99%

Transcriptome Profiling of HCT-116 Colorectal Cancer Cells with RNA Sequencing Reveals Novel Targets for Polyphenol Nano Curcumin

Azeez

Neri²,

Feizi³

et al. 2022

Molecules

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“…For example, myeloid-derived suppressor cells (MDSCs) were described as constraining T cell activation by exhausting cyst(e)ine in the TME . In order to overcome drug resistance and render drug-resistant cancer cells sensitive to traditional chemotherapy and immunotherapy, therapeutic targets emerging to surmount therapeutic resistance are found related to some ferroptosis pathways. , Increasing studies have elucidated that ferroptosis is an alternative for reversing the resistance of cisplatin, Temozolomide, docetaxel, etc. , Ferroptosis is able to interact with immune TME to perform potential cancer immunotherapy . Ferroptosis can selectively eradicate aggressive CSCs which possess the ability to self-renew, initiate tumors, and cause resistance to conventional anticancer agents in TME .…”

Section: Mechanism Of Ferroptosis Initiation For Fighting Against Can...mentioning

confidence: 99%

“…132 In order to overcome drug resistance and render drug-resistant cancer cells sensitive to traditional chemotherapy and immunotherapy, therapeutic targets emerging to surmount therapeutic resistance are found related to some ferroptosis pathways. 133,134 Increasing studies have elucidated that ferroptosis is an alternative for reversing the resistance of cisplatin, Temozolomide, docetaxel, etc. 134,135 Ferroptosis is able to interact with immune TME to perform potential cancer immunotherapy.…”

Section: System X Cmentioning

confidence: 99%

Ferroptosis-Driven Nanotherapeutics to Reverse Drug Resistance in Tumor Microenvironment

Zhu

Meng

Wang

et al. 2022

ACS Appl. Bio Mater.

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Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, is non-apoptotic programmed cell death highly relevant to tumor development. It was found to manipulate oncogenes and resistant mutations of cancer cells via lipid metabolism pathways converging on phospholipid glutathione peroxidase (GPX4) that squanders lipid peroxides (L-OOH) to block the iron-mediated reactions of peroxides, thus rendering resistant cancer cells vulnerable to ferroptotic cell death. By accumulating ROS and lipid peroxidation (LPO) products to lethal levels in tumor microenvironment (TME), ferroptosis-driven nanotherapeutics show a superior ability of eradicating aggressive malignancies than traditional therapeutic modalities, especially for the drug-resistant tumors with high metastasis tendency. Moreover, Fenton reaction, inhibition of GPX-4, and exogenous regulation of LPO are three major therapeutic strategies to induce ferroptosis in cancer cells, which were generally applied in ferroptosis-driven nanotherapeutics. In this review, we elaborate current trends of ferroptosisdriven nanotherapeutics to reverse drug resistance of tumors in anticancer fields at the intersection of cancer biology, materials science, and chemistry. Finally, their challenges and perspectives toward feasible translational studies are spotlighted, which would ignite the hope of anti-resistant cancer treatment.

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“…With the discovery of oncogenes and antioncogenes in the 1980s, the novel targeted treatment of imatinib was first approved in 2001 by the FDA [1][2][3]. The requirement of new anticancer medicines to the molecular groundwork is significantly higher than that of traditional chemotherapeutic drugs, of which their molecular mechanism of action was not identified empirically [3]. Kinases and phosphatases have key roles in controlling cellular functions [4].…”

Section: Introductionmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy

Li²,

Luo

et al. 2022

Mol Biomed

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The PI3K/AKT/mTOR and RAF/MEK/ERK pathways are commonly activated by mutations and chromosomal translocation in vital targets. The PI3K/AKT/mTOR signaling pathway is dysregulated in nearly all kinds of neoplasms, with the component in this pathway alternations. RAF/MEK/ERK signaling cascades are used to conduct signaling from the cell surface to the nucleus to mediate gene expression, cell cycle processes and apoptosis. RAS, B-Raf, PI3K, and PTEN are frequent upstream alternative sites. These mutations resulted in activated cell growth and downregulated cell apoptosis. The two pathways interact with each other to participate in tumorigenesis. PTEN alterations suppress RAF/MEK/ERK pathway activity via AKT phosphorylation and RAS inhibition. Several inhibitors targeting major components of these two pathways have been supported by the FDA. Dozens of agents in these two pathways have attracted great attention and have been assessed in clinical trials. The combination of small molecular inhibitors with traditional regimens has also been explored. Furthermore, dual inhibitors provide new insight into antitumor activity. This review will further comprehensively describe the genetic alterations in normal patients and tumor patients and discuss the role of targeted inhibitors in malignant neoplasm therapy. We hope this review will promote a comprehensive understanding of the role of the PI3K/AKT/mTOR and RAF/MEK/ERK signaling pathways in facilitating tumors and will help direct drug selection for tumor therapy.

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Modulating undruggable targets to overcome cancer therapy resistance

Cited by 20 publications

References 358 publications

Transcriptome Profiling of HCT-116 Colorectal Cancer Cells with RNA Sequencing Reveals Novel Targets for Polyphenol Nano Curcumin

Transcriptome Profiling of HCT-116 Colorectal Cancer Cells with RNA Sequencing Reveals Novel Targets for Polyphenol Nano Curcumin

Ferroptosis-Driven Nanotherapeutics to Reverse Drug Resistance in Tumor Microenvironment

Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy

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