Molecular Immunotherapy: Promising Approach to Treat Metastatic Colorectal Cancer by Targeting Resistant Cancer Cells or Cancer Stem Cells

Förster, Stefan; Radpour, Ramin

doi:10.3389/fonc.2020.569017

Cited by 22 publications

(17 citation statements)

References 89 publications

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“…However, it is often followed by tumour relapse and acquired chemotherapy-resistance. An effective drug for therapy and prognosis after surgery still does not exist [2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Hermanowicz

Szymanowska

Sieklucka

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and in women. The impact of the new pyrazolo [4,3-e]tetrazolo [1,5-b][1,2,4]triazine sulphonamide (MM-129) was evaluated against human colon cancer in vitro and in zebrafish xenografts. Our results show that this new synthesised compound effectively inhibits cell survival in BTK-dependent mechanism. Its effectiveness is much higher at a relatively low concentration as compared with the standard chemotherapy used for CRC, i.e. 5fluorouracil (5-FU). Flow cytometry analysis after annexin V-FITC and propidium iodide staining revealed that apoptosis was the main response of CRC cells to MM-129 treatment. We also found that MM-129 effectively inhibits tumour development in zebrafish embryo xenograft model, where it showed a markedly synergistic anticancer effect when used in combination with 5-FU. The above results suggest that this novel heterofused 1,2,4-triazine derivative may be a promising candidate for further evaluation as chemotherapeutic agent against CRC.

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“…However, it is often followed by tumour relapse and acquired chemotherapy-resistance. An effective drug for therapy and prognosis after surgery still does not exist [2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Hermanowicz

Szymanowska

Sieklucka

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In CSCs, the acquisition of genetic mutations and atypical epigenetic modifications are key underlying mechanisms involved in immunosurveillance and therapeutic resistance[ 56 ]. Overall, these factors grant CSCs resilience to chemotherapeutics and radiation[ 56 - 58 ]. The presence of CSCs have been detected in hematological malignancies[ 59 - 61 ], as well as in multiple solid cancers, including, glioblastoma[ 62 ], pancreatic[ 63 ], breast[ 64 ], ovarian[ 65 ] and liver[ 66 ].…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells

Mandhair¹,

Novak²,

Radpour³

2021

WJSC

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Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.

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“…LSCs escape the immune control by natural killer (NK) cells and CD8 + T cells through the expression of immune-inhibitory molecules by downregulating of critical molecules/pathways involved in immune recognition, or by the expression of “don’t eat me” signals, such as CD47 ( 4 ). Immune-checkpoints (ICs) are essential regulators of the immune system, through activation (stimulatory checkpoint molecules) or inhibition (inhibitory checkpoint molecules) of immune cells ( 5 , 6 ). The balance of stimulatory and inhibitory ligand/receptor interaction determines the amplitude and quality of the antigen-specific immune responses ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia

et al. 2021

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BackgroundImmune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML.MethodsTo analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1.ResultsWe observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells.ConclusionsOur results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML.

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Molecular Immunotherapy: Promising Approach to Treat Metastatic Colorectal Cancer by Targeting Resistant Cancer Cells or Cancer Stem Cells

Cited by 22 publications

References 89 publications

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells

Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia

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