The Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2) or novel coronavirus (COVID-19) infection has been declared world pandemic causing a worrisome number of deaths, especially ...among vulnerable citizens, in 209 countries around the world. Although several therapeutic molecules are being tested, no effective vaccines or specific treatments have been developed. Since the COVID-19 outbreak, different traditional herbal medicines with promising results have been used alone or in combination with conventional drugs to treat infected patients. Here, we review the recent findings regarding the use of natural products to prevent or treat COVID-19 infection. Furthermore, the mechanisms responsible for this preventive or therapeutic effect are discussed. We conducted literature research using PubMed, Google Scholar, Scopus, and WHO website. Dissertations and theses were not considered. Only the situation reports edited by the WHO were included. The different herbal products (extracts) and purified molecules may exert their anti-SARS-CoV-2 actions by direct inhibition of the virus replication or entry. Interestingly, some products may block the ACE-2 receptor or the serine protease TMPRRS2 required by SARS-CoV-2 to infect human cells. In addition, natural products were shown to inhibit the SARS-CoV-2 life-cycle related proteins such as papain-like or chymotrypsin-like proteases. In conclusion, we suggest that natural products could be used alone or in combination as alternative medicines to treat/prevent COVID-19 infection. Moreover, their structures may offer clues for the development of anti-SARS-CoV-2 drugs.
Resistance to Antibody-Drug Conjugates García-Alonso, Sara; Ocaña, Alberto; Pandiella, Atanasio
Cancer research (Chicago, Ill.),
05/2018, Letnik:
78, Številka:
9
Journal Article
Recenzirano
Antibody-drug conjugates (ADC) are multicomponent molecules constituted by an antibody covalently linked to a potent cytotoxic agent. ADCs combine high target specificity provided by the antibody ...together with strong antitumoral properties provided by the attached cytotoxic agent. At present, four ADCs have been approved and over 60 are being explored in clinical trials. Despite their effectiveness, resistance to these drugs unfortunately occurs. Efforts to understand the bases underlying such resistance are being carried out with the final purpose of counteracting them. In this review, we report described mechanisms of resistance to ADCs used in the clinic along with other potential ones that may contribute to resistance acquisition. We also discuss strategies to overcome resistance to ADCs.
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The neuregulins and their ErbB/HER receptors play essential roles in mammalian development and tissue homeostasis. In addition, deregulation of their function has been linked to the pathogenesis of ...diseases such as cancer or schizophrenia. These circumstances have stimulated research into the biology of this ligand-receptor system. Here we show the identification of programmed cell death protein-4 (PDCD4) as a novel neuregulin-ErbB signaling mediator. Phosphoproteomic analyses identified PDCD4 as protein whose phosphorylation increased in cells treated with neuregulin. Mutagenesis experiments defined serine 67 of PDCD4 as a site whose phosphorylation increased upon activation of neuregulin receptors. Phosphorylation of that site promoted degradation of PDCD4 by the proteasome, which depended on exit of PDCD4 from the nucleus to the cytosol. Mechanistic studies defined mTORC1 and ERK1/2 as routes implicated in neuregulin-induced serine 67 phosphorylation and PDCD4 degradation. Functionally, PDCD4 regulated several important biological functions of neuregulin, such as proliferation, migration, or invasion.
There has been substantial interest in HER2 intratumoral heterogeneity as an explanation for the development of resistance to anti-HER2 therapies in breast cancer, particularly to trastuzumab ...emtansine (T-DM1).
Through a literature-based approach, we discuss mechanisms of resistance to HER2-targeting antibody-drug conjugates (ADCs) in breast cancer.
We describe results from clinical studies reporting the effect of anti-HER2 strategies particularly ADCs and their mechanistic effect. We review biological findings underlying HER2 heterogeneity and its implication in the development of novel anti-HER2 drugs including new ADCs in clinical development like trastuzumab deruxtecan (DS-8201).
We suggest potential mechanisms to optimize these compounds and their future clinical implementation.
Expression of high levels of immune cells including neutrophils has been associated with detrimental outcome in several solid tumors and new strategies to decrease their presence and activity are ...currently under clinical development. Here, we review some of the relevant literature of the role of neutrophils in different stages of the oncogenic process including tumor initiation, growth, proliferation or metastatic spreading and also focus on how neutrophil counts or the neutrophil-to-lymphocyte ratio may be used as a prognostic and predictive biomarker. Strategies to avoid the deleterious effects of neutrophils in cancer and to reduce their activity are discussed. Examples for such strategies include inhibition of CXCR1 and CXCR2 to decrease migration of neutrophils to tumoral areas or the inhibition of granulocyte colony stimulating factor to decrease the amount of neutrophils which has shown efficacy in preclinical models.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exploitation of the protein degradation machinery as a therapeutic strategy to degrade oncogenic proteins is experiencing revolutionary advances with the development of proteolysis targeting chimeras ...(PROTACs). PROTACs are heterobifunctional structures consisting of a ligand that binds a protein to be degraded and a ligand for an E3 ubiquitin ligase. The bridging between the protein of interest and the E3 ligase mediated by the PROTAC facilitates ubiquitination of the protein and its proteasomal degradation. In this review we discuss the molecular medicine behind PROTAC mechanism of action, with special emphasis on recent developments and their potential translation to the clinical setting. Keywords: PROTACs, BET inhibitors, Proteasome, Ubiquitination, Protein degradation
Triple negative breast cancer (TNBC) is still an incurable disease despite the great scientific effort performed during the last years. The huge heterogeneity of this disease has motivated the ...evaluation of a great number of therapies against different molecular alterations. In this article, we review the biological bases of this entity and how the known molecular evidence supports the current preclinical and clinical development of new therapies. Special attention will be given to ongoing clinical studies and potential options for future drug combinations.
Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib ...targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor-positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale.
The human epidermal growth factor receptor 3 (HER3) is an ErbB/HER family member that dimerizes with other ErbB receptors such as HER2. Numerous agents against HER3 are in clinical development ...despite variable data for the prognostic impact of HER3 expression. Here we report a meta-analysis of the association of HER3 expression and survival in solid tumors.
PubMed was searched for studies evaluating expression of HER3 (as measured by immunohistochemistry) and overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (ORs) for death at 3 and 5 years. Data were pooled using the Mantel-Haenszel random-effect model. All statistical tests were two-sided.
Analysis included 12 studies: three that evaluated colorectal cancer, two that evaluated gastric cancer, two that evaluated breast cancer, and one each that evaluated melanoma, ovarian cancer, head and neck cancer, pancreatic cancer, and cervical cancer. The median percentage of cancers with HER3 overexpression was 42.2%. HER3 was associated with worse OS at both 3 years (OR = 2.24, 95% confidence interval CI = 1.77 to 2.83, P < .001) and 5 years (OR = 2.20, 95% CI = 1.75 to 2.76, P < .001). Among studies with common HER2 overexpression (breast, gastric, and ovarian cancers), the magnitude of effect of HER3 on OS was statistically significantly greater for both 3-year OS (OR = 3.12, 95% CI = 2.24 to 4.37) and 5-year OS (OR = 2.84, 95% CI = 2.09 to 3.88).
Expression of HER3 is associated with worse survival in solid tumors. The influence of HER3 may be greater in those tumors where HER2 is commonly overexpressed.
HER3 in cancer: from the bench to the bedside Gandullo-Sánchez, Lucía; Ocaéa, Alberto; Pandiella, Atanasio
Journal of experimental & clinical cancer research,
10/2022, Letnik:
41, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The HER3 protein, that belongs to the ErbB/HER receptor tyrosine kinase (RTK) family, is expressed in several types of tumors. That fact, together with the role of HER3 in promoting cell ...proliferation, implicate that targeting HER3 may have therapeutic relevance. Furthermore, expression and activation of HER3 has been linked to resistance to drugs that target other HER receptors such as agents that act on EGFR or HER2. In addition, HER3 has been associated to resistance to some chemotherapeutic drugs. Because of those circumstances, efforts to develop and test agents targeting HER3 have been carried out. Two types of agents targeting HER3 have been developed. The most abundant are antibodies or engineered antibody derivatives that specifically recognize the extracellular region of HER3. In addition, the use of aptamers specifically interacting with HER3, vaccines or HER3-targeting siRNAs have also been developed. Here we discuss the state of the art of the preclinical and clinical development of drugs aimed at targeting HER3 with therapeutic purposes. Keywords: HER3, Cancer therapy, Receptor tyrosine kinases
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