scholarly journals Revisiting the Immunological Aspects of Temozolomide Considering the Genetic Landscape and the Immune Microenvironment Composition of Glioblastoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Natalia Di Ianni ◽  
Martina Maffezzini ◽  
Marica Eoli ◽  
Serena Pellegatta
Keyword(s):  
Cancer Cells ◽  
Critical Role ◽  
Acquired Resistance ◽  
Therapeutic Approaches ◽  
Immunomodulatory Effects ◽  
First Line ◽  
Immune Microenvironment ◽  
Genetic Landscape ◽  
Peripheral Immune Response ◽  
Functional Alteration

The microenvironment (ME) plays a critical role in causing glioblastoma (GBM) to be a moving and incurable target. The main features governing the interaction between cancer cells and the ME include dependency, promotion, and in rare cases, even competition. In the original Stupp protocol, the alkylating agent temozolomide (TMZ) is the first-line chemotherapy drug to treat GBM, and it is broadly used together or after radiotherapy. Some studies have described TMZ as an adjuvant to other therapeutic approaches including immunotherapy because of its ability to induce an immunogenic death of cancer cells. TMZ also exerts immunomodulatory effects on the tumor and immune ME. These findings support the coexistence of two circuits, i.e., one that subverts local immunosuppressive mechanisms and another that exerts a harmful influence on the peripheral immune response. A bias toward the latter can drive the failure of treatments based on the combination of chemotherapy and immunotherapy approaches. In this review, we will reanalyze how intrinsic and acquired resistance to TMZ impacts the immunomodulatory effects previously described by way of inducing a functional alteration of local immune cells and promoting immunosuppression and how different components of the immune ME, with particular attention to tumor-associated macrophages and microglia, can cause TMZ resistance to circumvent potential local immunogenic mechanisms.

scholarly journals Overactivation of Akt Contributes to MEK Inhibitor Primary and Acquired Resistance in Colorectal Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1866 ◽  
Author(s):  
Tsubaki ◽  
Takeda ◽  
Noguchi ◽  
Jinushi ◽  
Seki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Critical Role ◽  
Pik3ca Mutation ◽  
Acquired Resistance ◽  
Mek Inhibitor ◽  
Blue Dye ◽  
Colorectal Cancer Cells ◽  
Inhibitor Resistance ◽  
Ht 29

RAS and BRAF-mutated colorectal cancers are associated with resistance to chemotherapy and poor prognosis, highlighting the need for new therapeutic strategies. Although these cancers sometimes respond to mitogen activated protein kinase kinase (MEK) inhibitor treatment, they often acquire resistance via mechanisms, which are poorly understood. Here, we investigated the mechanism of MEK inhibitor resistance in primary- and acquired-resistant cells. Cell viability was examined using the trypan blue dye exclusion assay. Protein expression was analyzed by western blotting. Somatic mutations in colorectal cancer cells were investigated using the polymerase chain reaction array. PD0325901 and trametinib induced cell death in LoVo and Colo-205 cells but not in DLD-1 and HT-29 cells, which have a PIK3CA mutation constitutively activating Akt and NF-κB. Treatment with PD0325901 and trametinib suppressed ERK1/2 activation in all four cell lines but only induced Akt and NF-κB activation in DLD-1 and HT-29 cells. Inhibition of Akt but not NF-κB, overcame MEK inhibitor resistance in DLD-1 and HT-29 cells. Acquired-resistant LoVo/PR, Colo-205/PR and LoVo/TR cells have constitutively active Akt due to a M1043V mutation in the kinase activation loop of PIK3CA and Akt inhibitor resensitized these cells to MEK inhibitor. These results demonstrate that the overactivation of Akt plays a critical role in MEK inhibitor primary and acquired resistance and implicate combined Akt/MEK inhibition as a potentially useful treatment for RAS/BRAF-mutated colorectal cancer.

scholarly journals Small Cell Lung Cancer: State of the Art of the Molecular and Genetic Landscape and Novel Perspective

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1723
Author(s):  
Valeria Denninghoff ◽  
Alessandro Russo ◽  
Diego de Miguel-Pérez ◽  
Umberto Malapelle ◽  
Amin Benyounes ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Metastatic Potential ◽  
Small Cell ◽  
Therapeutic Approaches ◽  
Small Cell Lung ◽  
First Line ◽  
Genetic Landscape ◽  
Novel Drug

Small cell lung cancer (SCLC) is a highly proliferative lung cancer that is not amenable to surgery in most cases due to the high metastatic potential. Precision medicine has not yet improved patients’ survival due to the lack of actionable mutations. Intra- and intertumoral heterogeneity allow the neoplasms to adapt to various microenvironments and treatments. Further studying this heterogeneous cancer might yield the discovery of actionable mutations. First-line SCLC treatment has added immunotherapy to its armamentarium. There has been renewed interest in SCLC, and numerous clinical trials are underway with novel therapeutic approaches. Understanding the molecular and genetic landscape of this heterogeneous and lethal disease will pave the way for novel drug development.

New therapeutic approaches for polymyositis and dermatomyositis

2011 ◽  
Vol 152 (39) ◽  
pp. 1552-1559 ◽  
Author(s):  
Katalin Dankó ◽  
Melinda Vincze
Keyword(s):  
Immunosuppressive Agents ◽  
Inflammatory Myopathy ◽  
Proximal Muscle ◽  
Therapeutic Approaches ◽  
First Line ◽  
New Therapeutic Approaches ◽  
Remission Period ◽  
Immune Mediated ◽  
Systemic Manifestations ◽  
Line Of Therapy

Inflammatory myopathies are chronic, immune-mediated diseases characterized with progressive proximal muscle weakness. They encompass a variety of syndromes with protean manifestations. The aims of therapy are to increase muscle strength, prevent the development of contractures, and to manage the systemic manifestations of the disease. This is a complex treatment which requires routine and wide knowledge. The most important task is to recognize the disease and guide the patient to immunologic center. Although the first line of therapy continues to include corticosteroids, there are a multitude of agents available for treating patients with myositis. There are several different immunosuppressive agents which may be applied alone or in combination with each other, as well as an increasing number of novel and exciting biologic agents targeting molecules participating in the pathogenesis of inflammatory myopathy. Physiotherapy and rehabilitation in the remission period may significantly improve the functional outcome of patients with these disorders. Orv. Hetil., 2011, 152, 1552–1559.

A Rational Sequencing of Anti-Angiogenic Agents as Second-Line Treatment Choice for mCRC Patients Progressing After a Bevacizumab-Based First Line

2020 ◽  
pp. 14-19
Author(s):  
Sara De Dosso
Keyword(s):  
Acquired Resistance ◽  
Predictive Biomarker ◽  
Cancer Therapies ◽  
Vascular Endothelial ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Vegf Pathway ◽  
Effective Choice ◽  
Endothelial Growth Factor

A large proportion of patients with metastatic colorectal cancer (mCRC) experience disease progression after first-line treatment with chemotherapy and bevacizumab, an anti-angiogenic agent, as a result of acquired resistance. However, blocking angiogenesis by targeted therapy towards the vascular endothelial growth factor (VEGF) pathway still forms an essential part of the second-line treatment strategy. Although three approved evidence-based choices for angiogenic agents (continuing treatment with bevacizumab, ramucirumab and aflibercept) are currently available in the second line, making the most effective choice is challenging due to the lack of studies directly comparing these agents. Moreover, despite huge investigational efforts, no predictive biomarker for anti-angiogenic cancer therapies could be identified so far.

scholarly journals Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

2021 ◽  
Vol 22 (15) ◽  
pp. 8117
Author(s):  
Nunzia D’Onofrio ◽  
Elisa Martino ◽  
Luigi Mele ◽  
Antonino Colloca ◽  
Martina Maione ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

scholarly journals Long non-coding RNA LINC00665 promotes gemcitabine resistance of Cholangiocarcinoma cells via regulating EMT and stemness properties through miR-424-5p/BCL9L axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Min Lu ◽  
Xinglei Qin ◽  
Yajun Zhou ◽  
Gang Li ◽  
Zhaoyang Liu ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Transcriptional Regulators ◽  
First Line ◽  
Protein Coding ◽  
Gemcitabine Resistance ◽  
Non Coding Rna ◽  
Sphere Formation ◽  
Long Non Coding Rna ◽  
Line Chemotherapy

AbstractGemcitabine is the first-line chemotherapy drug for cholangiocarcinoma (CCA), but acquired resistance has been frequently observed in CCA patients. To search for potential long noncoding RNAs (lncRNAs) involved in gemcitabine resistance, two gemcitabine resistant CCA cell lines were established and dysregulated lncRNAs were identified by lncRNA microarray. Long intergenic non-protein coding RNA 665 (LINC00665) were found to rank the top 10 upregulated lncRNAs in our study, and high LINC00665 expression was closely associated with poor prognosis and chemoresistance of CCA patients. Silencing LINC00665 in gemcitabine resistant CCA cells impaired gemcitabine tolerance, while enforced LINC00665 expression increased gemcitabine resistance of sensitive CCA cells. The gemcitabine resistant CCA cells showed increased EMT and stemness properties, and silencing LINC00665 suppressed sphere formation, migration, invasion and expression of EMT and stemness markers. In addition, Wnt/β-Catenin signaling was activated in gemcitabine resistant CCA cells, but LINC00665 knockdown suppressed Wnt/β-Catenin activation. B-cell CLL/lymphoma 9-like (BCL9L), the nucleus transcriptional regulators of Wnt/β-Catenin signaling, plays a key role in the nucleus translocation of β-Catenin and promotes β-Catenin-dependent transcription. In our study, we found that LINC00665 regulated BCL9L expression by acting as a molecular sponge for miR-424-5p. Moreover, silencing BCL9L or miR-424-5p overexpression suppressed gemcitabine resistance, EMT, stemness and Wnt/β-Catenin activation in resistant CCA cells. In conclusion, our results disclosed the important role of LINC00665 in gemcitabine resistance of CCA cells, and provided a new biomarker or therapeutic target for CCA treament.

scholarly journals Transcriptional coregualtor NUPR1 maintains tamoxifen resistance in breast cancer cells

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Lingling Wang ◽  
Jiashen Sun ◽  
Yueyuan Yin ◽  
Yanan Sun ◽  
Jinyi Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Endocrine Resistance ◽  
Autophagic Flux ◽  
Physical Interaction ◽  
Premature Senescence ◽  
Breast Cancers ◽  
Transcriptional Coregulator

AbstractTo support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.

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