Vascular toxicity associated with anti-angiogenic drugs

2020 ◽  
Vol 134 (18) ◽  
pp. 2503-2520
Author(s):  
Karla B. Neves ◽  
Augusto C. Montezano ◽  
Ninian N. Lang ◽  
Rhian M. Touyz
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Adenosine Diphosphate ◽  
No Production ◽  
Vascular Effects ◽  
Vegf Inhibitors ◽  
Vascular Toxicity ◽  
Endothelin System ◽  
Anti Cancer

Abstract Over the past two decades, the treatment of cancer has been revolutionised by the highly successful introduction of novel molecular targeted therapies and immunotherapies, including small-molecule kinase inhibitors and monoclonal antibodies that target angiogenesis by inhibiting vascular endothelial growth factor (VEGF) signaling pathways. Despite their anti-angiogenic and anti-cancer benefits, the use of VEGF inhibitors (VEGFi) and other tyrosine kinase inhibitors (TKIs) has been hampered by potent vascular toxicities especially hypertension and thromboembolism. Molecular processes underlying VEGFi-induced vascular toxicities still remain unclear but inhibition of endothelial NO synthase (eNOS), reduced nitric oxide (NO) production, oxidative stress, activation of the endothelin system, and rarefaction have been implicated. However, the pathophysiological mechanisms still remain elusive and there is an urgent need to better understand exactly how anti-angiogenic drugs cause hypertension and other cardiovascular diseases (CVDs). This is especially important because VEGFi are increasingly being used in combination with other anti-cancer dugs, such as immunotherapies (immune checkpoint inhibitors (ICIs)), other TKIs, drugs that inhibit epigenetic processes (histone deacetylase (HDAC) inhibitor) and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, which may themselves induce cardiovascular injury. Here, we discuss vascular toxicities associated with TKIs, especially VEGFi, and provide an up-to-date overview on molecular mechanisms underlying VEGFi-induced vascular toxicity and cardiovascular sequelae. We also review the vascular effects of VEGFi when used in combination with other modern anti-cancer drugs.

scholarly journals Vascular effects of cancer treatments

2020 ◽  
Vol 25 (3) ◽  
pp. 226-234 ◽  
Author(s):  
Umberto Campia
Keyword(s):  
Cancer Biology ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Proteasome Inhibitors ◽  
Clinical Manifestations ◽  
Team Approach ◽  
Vascular Effects ◽  
Cancer Treatments ◽  
Vascular Toxicity ◽  
Peripheral Ischemia

Chemotherapy, alone or in association with radiation therapy, has represented the cornerstone of cancer treatment for decades. However, in the last several years, an unprecedented progress in the understanding of cancer biology and the discovery of novel therapeutic targets have led to a paradigm shift in the management of patients with neoplastic diseases. The introduction of tyrosine kinase inhibitors, vascular endothelial growth factor pathway inhibitors, immunomodulatory agents, proteasome inhibitors, immune checkpoint inhibitors, and chimeric antigen receptor T cells, among others, has been associated with prolonged survival in many forms of cancer. A common feature of both chemotherapy and novel cancer treatments is the frequent occurrence of vascular toxicity, mainly mediated by injury to the endothelium. While the mechanisms may vary between agents, the clinical manifestations may overlap and range from hypertension, vasospastic and thrombotic arterial events (myocardial ischemia and infarction, peripheral ischemia, and limb gangrene), venous thromboembolism (deep vein thrombosis and pulmonary embolism) to capillary leak syndrome. Therefore, the effective management of patients with cancer requires a multidisciplinary team approach in which oncologist and cardiovascular medicine specialists work together to prevent, detect, and minimize acute vascular toxicity and long-term consequences of cancer therapy.

scholarly journals Molecular Mechanisms of the Anti-Cancer Effects of Isothiocyanates from Cruciferous Vegetables in Bladder Cancer

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 575 ◽  
Author(s):  
Tomhiro Mastuo ◽  
Yasuyoshi Miyata ◽  
Tsutomu Yuno ◽  
Yuta Mukae ◽  
Asato Otsubo ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Allyl Isothiocyanate ◽  
Cruciferous Vegetables ◽  
Current Trends ◽  
Carcinogenic Potential ◽  
Anti Cancer ◽  
Future Direction

Bladder cancer (BC) is a representative of urological cancer with a high recurrence and metastasis potential. Currently, cisplatin-based chemotherapy and immune checkpoint inhibitors are used as standard therapy in patients with advanced/metastatic BC. However, these therapies often show severe adverse events, and prolongation of survival is unsatisfactory. Therefore, a treatment strategy using natural compounds is of great interest. In this review, we focused on the anti-cancer effects of isothiocyanates (ITCs) derived from cruciferous vegetables, which are widely cultivated and consumed in many regions worldwide. Specifically, we discuss the anti-cancer effects of four ITC compounds—allyl isothiocyanate, benzyl isothiocyanate, sulforaphane, and phenethyl isothiocyanate—in BC; the molecular mechanisms underlying their anti-cancer effects; current trends and future direction of ITC-based treatment strategies; and the carcinogenic potential of ITCs. We also discuss the advantages and limitations of each ITC in BC treatment, furthering the consideration of ITCs in treatment strategies and for improving the prognosis of patients with BC.

Molecular mechanisms for vascular complications of targeted cancer therapies

2016 ◽  
Vol 130 (20) ◽  
pp. 1763-1779 ◽  
Author(s):  
Srila Gopal ◽  
Kenneth B. Miller ◽  
Iris Z. Jaffe
Keyword(s):  
Cancer Patients ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Vascular Complications ◽  
Vascular Complication ◽  
Cancer Therapies ◽  
Vegf Inhibitors ◽  
Increased Risk ◽  
Anti Cancer ◽  
Targeted Cancer Therapies

Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future.

scholarly journals Challenges in the Current Management of Hepatocellular Carcinoma

2021 ◽  
Vol 6 (04) ◽  
pp. 269-274
Author(s):  
Soumya Jogi ◽  
Radha Varanasi ◽  
Sravani S Bantu ◽  
Sudha Saduvala ◽  
Ashish Manne
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Function ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Staging System ◽  
Convincing Evidence ◽  
Locoregional Therapy ◽  
Vegf Inhibitors ◽  
Stereotactic Radiation

Management of hepatocellular carcinoma (HCC) is complicated. Barcelona Clinic Liver Cancer (BCLC) staging system is widely used in risk stratifying HCC. It is different from anatomic staging (TNM) used in other cancers and is based on the liver function (Child-Pugh Score) and performance status at diagnosis along with tumor characteristics like size/number of primary, vascular invasion, and distant metastasis. Guidelines proposed by various liver societies help the treating physician select first-line therapy, but there are many limitations to them. Lack of reliable biomarkers that give objective information to monitor the response other than alpha-fetoprotein or radiological response is hurting the management strategies. There are no ideal predictors for recurrence and residual microscopic disease, especially after locoregional therapy (LRT) like surgical resection, ablation, transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic radiation therapy (SBRT). Also, there is no convincing evidence to use adjunct therapy along with LRT in localized HCC. There is a need to identify the subset of HCC that would benefit from peri-procedural therapy. Recommendations for treating advanced HCC with macrovascular invasion is not uniform across the guidelines. Some propose LRT (TACE and/or TARE) or recommend systemic therapy only like tyrosine-kinase inhibitors (TKI) or Immune-checkpoint inhibitors (ICI). A considerable portion of patients have poor liver function (Child-Pugh Score C) at diagnosis. In this era of medicine, we should give them options other than supportive care, but unfortunately, it is the preferred option. This population needs special attention in trials. In current practice, there only 2-3 classes of drugs available like TKI, ICI, and vascular endothelial growth factor (VEGF) inhibitors. There is a need to explore more classes of liver-friendly drugs in treating HCC, and the enrolment of patients in clinical trials must be advised in the guidelines.

Abstract 258: Angiotensin 1-7 Attenuates Endothelin-1-Induced Endothelial Cell Inflammation and Growth Through Nitric Oxide Production and Activation of Mas and EndothelinB Receptors

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Hiba Yusuf ◽  
Augusto C Montezano ◽  
Glaucia E Callera ◽  
Aurille Nguyen Dinh Cat ◽  
Robson A Santos ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
No Production ◽  
Beneficial Effects ◽  
Mas Receptor ◽  
Mediated Effects ◽  
Endothelin System ◽  
Etb Receptor

In pulmonary hypertension, where the endothelin system plays a major role, the vasoprotective axis of the rennin angiotensin system (ACE2-Ang (1-7)-Mas) seems to be protective. However, the exact mechanisms are still elusive and whether Ang 1-7 counterbalancing effects are beyond interactions with Ang II system is unknown. In this study, we assessed whether Ang 1-7 influences/interacts with the ET-1 system in endothelial cells. Cultured human microvascular endothelial cells (HMEC) were studied. HMEC were stimulated with ET-1 (10-7 mol/L) in the absence and presence of Ang 1-7 (10-7 mol/L), BQ788 (an ETBR antagonist), BQ 123 (an ETAR antagonist) and A779 (Mas receptor inhibitor) (10-6 mol/L). Expression of pro-inflammatory mediator (VCAM-1), cell growth marker (PCNA), Mas, ETBR expression and eNOS activation was determined by immunoblotting. ET-1 significantly increased expression of VCAM-1 (138.90% vs control, p<0.05) and PCNA (125% vs control, p<0.05). Ang 1-7 alone did not modulate pro-inflammatory and growth mediators, but significantly inhibited the effects of ET-1 on VCAM-1 (95.55%) and PCNA (103.83%) expression, an effect mediated by Mas receptor activation (after A779: VCAM-1: 226.15%; PCNA: 120% vs control, p<0.05). Ang 1-7 increased NO production (Ctl: 7.5 vs Ang 1-7: 20 RFU/ug of protein, by microfluorescence). Inhibition of Ang 1-7-induced NO production by L-NAME, inhibited Ang 1-7-mediated effects on ET-1-induced VCAM-1 (160%) and PCNA (125%), p<0.05. Ang 1-7 significantly increased expression of ETB receptors (175.63% vs control, p<0.05), an effect attenuated by A779. Ang 1-7 (166.94% vs control, p<0.05) and ET-1 (146.04% vs control, p<0.05) increased eNOS phosphorylation in HMEC. Blockade of Mas and ETB receptor inhibited Ang 1-7 and ET-1 effects on eNOS activation. BQ123, but not BQ788, blocked ET-1-stimulated inflammation/growth in HMEC (VCAM-1: 75%, PCNA: 100%, p<0.05). In conclusion, Ang 1-7 negatively modulates proinflammatory and mitogenic actions of ET-1, through crosstalk between Mas and ETB receptors, and increase in NO production. These data highlight some molecular mechanisms whereby Ang 1-7 may exert beneficial effects in pulmonary hypertension and suggests a novel mechanism for Ang 1-7 signalling in HMEC.

scholarly journals Molecular mechanisms of the anti-cancer drug, LY2874455, in overcoming the FGFR4 mutation-based resistance

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fariba Dehghanian ◽  
Shahryar Alavi
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Substrate Binding ◽  
Growth Factor Receptor ◽  
Binding Pocket ◽  
Cancer Drug ◽  
Inhibition Mechanism ◽  
Wild Type ◽  
Substrate Binding Pocket ◽  
Anti Cancer

AbstractIn recent years, many strategies have been used to overcome the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKIs) resistance caused by different mutations. LY2874455 (or 6LF) is a pan-FGFR inhibitor which is identified as the most efficient TKI for all resistant mutations in FGFRs. Here, we perform a comparative dynamics study of wild type (WT) and the FGFR4 V550L mutant for better understanding of the 6LF inhibition mechanism. Our results confirm that the pan-FGFR inhibitor 6LF can bind efficiently to both WT and V550L FGFR4. Moreover, the communication network analysis indicates that in apo-WT FGFR4, αD–αE loop behaves like a switch between open and close states of the substrate-binding pocket in searching of its ligand. In contrast, V550L mutation induces the active conformation of the FGFR4 substrate-binding pocket through disruption of αD–αE loop and αG helix anti-correlation. Interestingly, 6LF binding causes the rigidity of hinge and αD helix regions, which results in overcoming V550L induced resistance. Collectively, the results of this study would be informative for designing more efficient TKIs for more effective targeting of the FGFR signaling pathway.

scholarly journals Endocrine complications of new anticancer therapies

2021 ◽  
Vol 75 ◽  
pp. 191-198
Author(s):  
Michał Miner ◽  
Michał Elbaum ◽  
Aleksandra Jawiarczyk-Przybyłowska ◽  
Eliza Kubicka
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Myelogenous Leukemia ◽  
Cytotoxic T Cell ◽  
Cancer Therapies ◽  
Programmed Death ◽  
New Cancer Therapies ◽  
Endocrine Complications

Studying and analyzing of complex molecular mechanisms and immunological processes of cancer enables oncology to introduce new cancer therapies. In the treatment of cancer, we successively increase the use of targeted therapies with tyrosine kinase inhibitors and mTOR inhibitors and immunotherapy using checkpoint inhibitors CTLA-4 (cytotoxic T-cell antigen-4) and PD-1/PD-L1 (programmed death receptor 1/programmed death ligand 1). New anticancer drugs gradually replace conventional chemotherapy and have already found application in the treatment of many cancers, including thyroid cancer, hepatocellular carcinoma, non-small cell lung cancer, kidney cancer, bladder cancer, melanoma, breast cancer, acute and chronic myelogenous leukemia. The use of these drugs is less toxic than classical chemotherapy, but it can cause gastrointestinal, cardiovascular, respiratory, skin and endocrine complications. Most of the side effects of new cancer therapies are mild and moderate disorders, however some might be severe and life-threatening. Endocrinopathies are one of the more common side effects of these treatments. They can affect many endocrine glands (pituitary, thyroid, parathyroid, adrenal, pancreas) and cause both transient and permanent disorders.

Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention

2008 ◽  
Vol 114 (5) ◽  
pp. 361-374 ◽  
Author(s):  
Weidong Zhu ◽  
Kenneth K. Y. Cheng ◽  
Paul M. Vanhoutte ◽  
Karen S. L. Lam ◽  
Aimin Xu
Keyword(s):  
Cell Activation ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Cell Transformation ◽  
Foam Cell ◽  
Vascular Diseases ◽  
No Production ◽  
Endothelial Cell Activation ◽  
Vascular Effects ◽  
Insulin Sensitizer

Adiponectin is a major adipocyte-secreted adipokine abundantly present in the circulation as three distinct oligomeric complexes. In addition to its role as an insulin sensitizer, mounting evidence suggests that adiponectin is an important player in maintaining vascular homoeostasis. Numerous epidemiological studies based on different ethnic groups have identified adiponectin deficiency (hypoadiponectinaemia) as an independent risk factor for endothelial dysfunction, hypertension, coronary heart disease, myocardial infarction and other cardiovascular complications. Conversely, elevation of circulating adiponectin concentrations by either genetic or pharmacological approaches can alleviate various vascular dysfunctions in animal models. Adiponectin exerts its vasculoprotective effects through its direct actions in the vascular system, such as increasing endothelial NO production, inhibiting endothelial cell activation and endothelium–leucocyte interaction, enhancing phagocytosis, and suppressing macrophage activation, macrophage-to-foam cell transformation and platelet aggregation. In addition, adiponectin reduces neointima formation through an oligomerization-dependent inhibition of smooth muscle proliferation. The present review highlights recent research advances in unveiling the molecular mechanisms that underpin the vascular actions of adiponectin and discusses the potential strategies of using adiponectin or its signalling pathways as therapeutic targets to combat obesity-related metabolic and vascular diseases.

scholarly journals Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5981
Author(s):  
Pablo Álvarez Ballesteros ◽  
Jesús Chamorro ◽  
María San Román-Gil ◽  
Javier Pozas ◽  
Victoria Gómez Dos Santos ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.

Immune Checkpoint Inhibitors: Basics and Challenges

2019 ◽  
Vol 26 (17) ◽  
pp. 3009-3025 ◽  
Author(s):  
Bin Li ◽  
Ho Lam Chan ◽  
Pingping Chen
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Complete Response ◽  
Modern World ◽  
Basic Principles ◽  
Mutation Status ◽  
Anti Cancer ◽  
Cancer Types ◽  
Shed Light

Cancer is one of the most deadly diseases in the modern world. The last decade has witnessed dramatic advances in cancer treatment through immunotherapy. One extremely promising means to achieve anti-cancer immunity is to block the immune checkpoint pathways – mechanisms adopted by cancer cells to disguise themselves as regular components of the human body. Many review articles have described a variety of agents that are currently under extensive clinical evaluation. However, while checkpoint blockade is universally effective against a broad spectrum of cancer types and is mostly unrestricted by the mutation status of certain genes, only a minority of patients achieve a complete response. In this review, we summarize the basic principles of immune checkpoint inhibitors in both antibody and smallmolecule forms and also discuss potential mechanisms of resistance, which may shed light on further investigation to achieve higher clinical efficacy for these inhibitors.

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