CYP1B1 as a therapeutic target in cardio-oncology

Abstract Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.

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Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms19123950 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3950 ◽

Cited By ~ 27

Author(s):

Marilina García-Aranda ◽

Elisabet Pérez-Ruiz ◽

Maximino Redondo

Keyword(s):

Cancer Treatment ◽

World Health ◽

Apoptosis Resistance ◽

Hallmarks Of Cancer ◽

Cancer Treatments ◽

Over Expression ◽

Promising Strategy ◽

Anti Cancer ◽

Health Organization

Abstract: According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. The identification of novel targets for cancer treatment is an area of intense work that has led Bcl-2 over-expression to be proposed as one of the hallmarks of cancer and Bcl-2 inhibition as a promising strategy for cancer treatment. In this review, we describe the different pathways related to programmed cell death, the role of Bcl-2 family members in apoptosis resistance to anti-cancer treatments, and the potential utility of Bcl-2 inhibitors to overcome resistance to chemo- and immunotherapy.

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Innovatory role of nanomaterials as bio-tools for treatment of cancer

Reviews in Inorganic Chemistry ◽

10.1515/revic-2020-0015 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Khuram Shahzad Ahmad ◽

Muntaha Talat ◽

Shaan Bibi Jaffri ◽

Neelofer Shaheen

Keyword(s):

Cancer Treatment ◽

Cancer Therapeutics ◽

Physicochemical Characteristics ◽

Global Scale ◽

Current Review ◽

Anti Cancer ◽

Different Types ◽

Cancerous Cells

AbstractConventional treatment modes like chemotherapy, thermal and radiations aimed at cancerous cells eradication are marked by destruction pointing the employment of nanomaterials as sustainable and auspicious materials for saving human lives. Cancer has been deemed as the second leading cause of death on a global scale. Nanomaterials employment in cancer treatment is based on the utilization of their inherent physicochemical characteristics in addition to their modification for using as nano-carriers and nano-vehicles eluted with anti-cancer drugs. Current work has reviewed the significant role of different types of nanomaterials in cancer therapeutics and diagnostics in a systematic way. Compilation of review has been done by analyzing voluminous investigations employing ERIC, MEDLINE, NHS Evidence and Web of Science databases. Search engines used were Google scholar, Jstore and PubMed. Current review is suggestive of the remarkable performance of nanomaterials making them candidates for cancer treatment for substitution of destructive treatment modes through investigation of their physicochemical characteristics, utilization outputs and long term impacts in patients.

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Synthesis, characterization and anti-cancer applications of ytterbium doped gadolinium molybdate nanophosphor compound

Materials Express ◽

10.1166/mex.2019.1572 ◽

2019 ◽

Vol 9 (8) ◽

pp. 882-894

Author(s):

Jahnavi Rama Madhuri Kamaraju ◽

Raghavendra Rao Kanchi ◽

Rajesh Kumar Borra ◽

Padma Suvarna Reniguntla ◽

Satyanarayana Rentala

Keyword(s):

Breast Cancer ◽

Cancer Treatment ◽

Cancer Cells ◽

Cancer Diagnosis ◽

Breast Cancer Cells ◽

Mri Contrast Agents ◽

Gadolinium Complexes ◽

Anti Cancer ◽

Gadolinium Molybdate

Nanophosphor compounds with both diagnostic and therapeutic functions are potential for cancer diagnosis and treatment. Lanthanide complexes play a crucial role in cancer diagnosis and therapy. Gadolinium-complexes are commonly used as magnetic resonance imaging (MRI) contrast agents for cancer imaging. The role of a lanthanide, Ytterbium (Yb) in cancer treatment is not unknown. The present work focuses on finding the role of Yb when doped into Gadolinium complexes in cancer treatment. Our results demonstrate that Yb doped Gadolinium molybdate coated with biocompatible silica, effectively inhibited the viability of breast cancer cells after 24 and 48 h of treatment in in vitro, and in contrast the nanophosphor compounds did not affect the viability of healthy cells. Yb doped Gadolinium molybdate also up-regulated apoptotic genes in breast cancer cells. Hence we propose that Yb doped Gadolinium molybdate is a promising theranostic compound. To the best of our knowledge, this is the first report showing anti-cancer nature of Ytterbium-doped into Gadolinium nanophosphors.

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The role of microvesicles in cancer progression and drug resistance

Biochemical Society Transactions ◽

10.1042/bst20120273 ◽

2013 ◽

Vol 41 (1) ◽

pp. 293-298 ◽

Cited By ~ 24

Author(s):

Samireh Jorfi ◽

Jameel M. Inal

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Cancer Progression ◽

Chemotherapeutic Agents ◽

Malignant Cells ◽

Intercellular Transport ◽

Wide Range ◽

Anti Cancer ◽

Mdr Multidrug Resistance

Microvesicles are shed constitutively, or upon activation, from both normal and malignant cells. The process is dependent on an increase in cytosolic Ca2+, which activates different enzymes, resulting in depolymerization of the actin cytoskeleton and release of the vesicles. Drug resistance can be defined as the ability of cancer cells to survive exposure to a wide range of anti-cancer drugs, and anti-tumour chemotherapeutic treatments are often impaired by innate or acquired MDR (multidrug resistance). Microvesicles released upon chemotherapeutic agents prevent the drugs from reaching their targets and also mediate intercellular transport of MDR proteins.

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ERK: A Double-Edged Sword in Cancer. ERK-Dependent Apoptosis as a Potential Therapeutic Strategy for Cancer

Cells ◽

10.3390/cells10102509 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2509

Author(s):

Reiko Sugiura ◽

Ryosuke Satoh ◽

Teruaki Takasaki

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Tumor Cell Death ◽

Cancer Treatments ◽

Erk Activation ◽

Cellular Processes ◽

Dual Specificity ◽

Anti Cancer ◽

Dual Specificity Phosphatases

The RAF/MEK/ERK signaling pathway regulates diverse cellular processes as exemplified by cell proliferation, differentiation, motility, and survival. Activation of ERK1/2 generally promotes cell proliferation, and its deregulated activity is a hallmark of many cancers. Therefore, components and regulators of the ERK pathway are considered potential therapeutic targets for cancer, and inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic. Notably, ERK1/2 kinases also have pro-apoptotic functions under certain conditions and enhanced ERK1/2 signaling can cause tumor cell death. Although the repertoire of the compounds which mediate ERK activation and apoptosis is expanding, and various anti-cancer compounds induce ERK activation while exerting their anti-proliferative effects, the mechanisms underlying ERK1/2-mediated cell death are still vague. Recent studies highlight the importance of dual-specificity phosphatases (DUSPs) in determining the pro- versus anti-apoptotic function of ERK in cancer. In this review, we will summarize the recent major findings in understanding the role of ERK in apoptosis, focusing on the major compounds mediating ERK-dependent apoptosis. Studies that further define the molecular targets of these compounds relevant to cell death will be essential to harnessing these compounds for developing effective cancer treatments.

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OvirusTdb: A Repository of Oncolytic Viruses used in Cancer Treatment

10.1101/2020.01.08.896720 ◽

2020 ◽

Author(s):

Anjali Lathwal ◽

Rajesh Kumar ◽

Gajendra P.S. Raghava

Keyword(s):

Cancer Treatment ◽

Cancer Cell ◽

Oncolytic Virus ◽

Cancer Cell Line ◽

Chemotherapeutic Agents ◽

Oncolytic Viruses ◽

Virus Species ◽

Cancer Cell Death ◽

Anti Cancer ◽

Fight Against Cancer

AbstractOne of the emerging technologies to fight against cancer is oncolytic virus-based immunotherapy which directly lysis tumor cells. Recently, the FDA approved an oncolytic virus named T-vec for the treatment of melanoma; several hundred other viruses are in clinical trials. In order to facilitate the scientific community to fight against cancer, we build a repository of oncolytic viruses called OvirusTdb (https://webs.iiitd.edu.in/raghava/ovirustdb/). This is a manually curated repository where information is curated from research papers and patents. The current version of the repository maintains comprehensive information on therapeutically important oncolytic viruses with 5927 records where each record has 25 fields such as the virus species, cancer cell line, synergism with anti-cancer drugs, and many more. It stores information on 09 types of DNA and 15 types of RNA viruses; 300 recombinant and 09 wildtype viral strains; tested against 124 cancer types and 427 cancer cell lines. Approximately, 1047 records show improved anti-cancer response using combinatorial approach of chemotherapeutic agents with virus strains. Nearly, 3243 and 1506 records show cancer cell death via apoptosis induction and immune activation, respectively. In summary, a user-friendly web repository of oncolytic viruses for information retrieval and analysis have been developed to facilitate researchers in designing and discovering new oncolytic viruses for effective cancer treatment.

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Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature

Frontiers in Oncology ◽

10.3389/fonc.2020.612802 ◽

2021 ◽

Vol 10 ◽

Cited By ~ 2

Author(s):

Aukie Hooglugt ◽

Miesje M. van der Stoel ◽

Reinier A. Boon ◽

Stephan Huveneers

Keyword(s):

Tumor Microenvironment ◽

Tumor Metastasis ◽

Lymphatic Vessels ◽

Cancer Therapies ◽

Tumor Cell Growth ◽

Vascular Normalization ◽

Cancer Treatments ◽

Anti Cancer ◽

Tumor Endothelium

Solid tumors are dependent on vascularization for their growth. The hypoxic, stiff, and pro-angiogenic tumor microenvironment induces angiogenesis, giving rise to an immature, proliferative, and permeable vasculature. The tumor vessels promote tumor metastasis and complicate delivery of anti-cancer therapies. In many types of tumors, YAP/TAZ activation is correlated with increased levels of angiogenesis. In addition, endothelial YAP/TAZ activation is important for the formation of new blood and lymphatic vessels during development. Oncogenic activation of YAP/TAZ in tumor cell growth and invasion has been studied in great detail, however the role of YAP/TAZ within the tumor endothelium remains insufficiently understood, which complicates therapeutic strategies aimed at targeting YAP/TAZ in cancer. Here, we overview the upstream signals from the tumor microenvironment that control endothelial YAP/TAZ activation and explore the role of their downstream targets in driving tumor angiogenesis. We further discuss the potential for anti-cancer treatments and vascular normalization strategies to improve tumor therapies.

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Advances and challenges in cancer treatment and nutraceutical prevention: the possible role of dietary phenols in BRCA regulation

Phytochemistry Reviews ◽

10.1007/s11101-021-09771-3 ◽

2021 ◽

Author(s):

Haroon Khan ◽

Fabiana Labanca ◽

Hammad Ullah ◽

Yaseen Hussain ◽

Nikolay T. Tzvetkov ◽

...

Keyword(s):

Cell Cycle ◽

Natural Products ◽

Cancer Treatment ◽

Clinical Aspects ◽

Anti Cancer ◽

Brca 1 ◽

Brca 2 ◽

The Impact ◽

Cancer Activity

AbstractOver the years, the attention towards the role of phytochemicals in dietary natural products in reducing the risk of developing cancer is rising. Cancer is the second primary cause of mortality worldwide. The current therapeutic options for cancer treatment are surgical excision, immunotherapy, chemotherapy, and radiotherapy. Unfortunately, in case of metastases or chemoresistance, the treatment options become very limited. Despite the advances in medical and pharmaceutical sciences, the impact of available treatments on survival is not satisfactory. Recently, natural products are a great deal of interest as potential anti-cancer agents. Among them, phenolic compounds have gained a great deal of interest, thanks to their anti-cancer activity. The present review focuses on the suppression of cancer by targeting BRCA gene expression using dietary polyphenols, as well as the clinical aspects of polyphenolic agents in cancer therapy. They regulate specific key processes involved in cancer progression and modulate the expression of oncogenic proteins, like p27, p21, and p53, which may lead to apoptosis, cell cycle arrest, inhibition of cell proliferation, and, consequently, cancer suppression. Thus, one of the mechanisms underlying the anti-cancer activity of phenolics involves the regulation of tumor suppressor genes. Among them, the BRCA genes, with the two forms (BRCA-1 and BRCA-2), play a pivotal role in cancer protection and prevention. BRCA germline mutations are associated with an increased risk of developing several types of cancers, including ovarian, breast, and prostate cancers. BRCA genes also play a key role in the sensitivity and response of cancer cells to specific pharmacological treatments. As the importance of BRCA-1 and BRCA-2 in reducing cancer invasiveness, repairing DNA damages, oncosoppression, and cell cycle checkpoint, their regulation by natural molecules has been examined.

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Possible Involvement of Mitochondrial Dysfunction and Oxidative Stress in a Cellular Model of NAFLD Progression Induced by Benzo[a]pyrene/Ethanol CoExposure

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4396403 ◽

2018 ◽

Vol 2018 ◽

pp. 1-18 ◽

Cited By ~ 12

Author(s):

Simon Bucher ◽

Dounia Le Guillou ◽

Julien Allard ◽

Grégory Pinon ◽

Karima Begriche ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Respiration ◽

Mitochondrial Respiratory Chain ◽

Ros Generation ◽

Nonalcoholic Fatty Liver ◽

Aryl Hydrocarbon ◽

Heparg Cells ◽

Mitochondrial Respiratory Chain Activity ◽

Respiratory Chain Activity

Exposure to xenobiotics could favor the transition of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis in obese patients. Recently, we showed in different models of NAFL that benzo[a]pyrene (B[a]P) and ethanol coexposure induced a steatohepatitis-like state. One model was HepaRG cells incubated with stearate and oleate for 2 weeks. In the present study, we wished to determine in this model whether mitochondrial dysfunction and reactive oxygen species (ROS) overproduction could be involved in the occurrence of this steatohepatitis-like state. CRISPR/Cas9-modified cells were also used to specify the role of aryl hydrocarbon receptor (AhR), which is potently activated by B[a]P. Thus, nonsteatotic and steatotic HepaRG cells were treated with B[a]P, ethanol, or both molecules for 2 weeks. B[a]P/ethanol coexposure reduced mitochondrial respiratory chain activity, mitochondrial respiration, and mitochondrial DNA levels and induced ROS overproduction in steatotic HepaRG cells. These deleterious effects were less marked or absent in steatotic cells treated with B[a]P alone or ethanol alone and in nonsteatotic cells treated with B[a]P/ethanol. Our study also disclosed that B[a]P/ethanol-induced impairment of mitochondrial respiration was dependent on AhR activation. Hence, mitochondrial dysfunction and ROS generation could explain the occurrence of a steatohepatitis-like state in steatotic HepaRG cells exposed to B[a]P and ethanol.

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More than Just an Immunosuppressant: The Emerging Role of FTY720 as a Novel Inducer of ROS and Apoptosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4397159 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 9

Author(s):

Teruaki Takasaki ◽

Kanako Hagihara ◽

Ryosuke Satoh ◽

Reiko Sugiura

Keyword(s):

Cancer Treatment ◽

Defense Mechanisms ◽

Chemotherapeutic Agents ◽

Future Directions ◽

Receptor Modulator ◽

Cystine Transporter ◽

Sphingosine 1 Phosphate ◽

S1p Receptor ◽

Fingolimod Hydrochloride

Fingolimod hydrochloride (FTY720) is a first-in-class of sphingosine-1-phosphate (S1P) receptor modulator approved to treat multiple sclerosis by its phosphorylated form (FTY720-P). Recently, a novel role of FTY720 as a potential anticancer drug has emerged. One of the anticancer mechanisms of FTY720 involves the induction of reactive oxygen species (ROS) and subsequent apoptosis, which is largely independent of its property as an S1P modulator. ROS have been considered as a double-edged sword in tumor initiation/progression. Intriguingly, prooxidant therapies have attracted much attention due to its efficacy in cancer treatment. These strategies include diverse chemotherapeutic agents and molecular targeted drugs such as sulfasalazine which inhibits the CD44v-xCT (cystine transporter) axis. In this review, we introduce our recent discoveries using a chemical genomics approach to uncover a signaling network relevant to FTY720-mediated ROS signaling and apoptosis, thereby proposing new potential targets for combination therapy as a means to enhance the antitumor efficacy of FTY720 as a ROS generator. We extend our knowledge by summarizing various measures targeting the vulnerability of cancer cells’ defense mechanisms against oxidative stress. Future directions that may lead to the best use of FTY720 and ROS-targeted strategies as a promising cancer treatment are also discussed.

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