Stress responses as master keys to epigenomic changes in transcriptome and metabolome for cancer etiology and therapeutics

2021 ◽  
Author(s):  
Atanu Mondal ◽  
Apoorva Bhattacharya ◽  
Vipin Singh ◽  
Shruti Pandita ◽  
Albino Bacolla ◽  
...  
Keyword(s):  
Stress Response ◽  
Cancer Cells ◽  
Stress Responses ◽  
Current Knowledge ◽  
Cancer Therapeutics ◽  
Molecular Architecture ◽  
Cancer Etiology ◽  
Treatment Scenario ◽  
Anti Cancer ◽  
Novel Therapeutic Strategies

From initiation through progression, cancer cells are subjected to a magnitude of endogenous and exogenous stresses, which aid in their neoplastic transformation. Exposure to these classes of stress induces imbalance in cellular homeostasis and, in response, cancer cells employ informative adaptive mechanisms to rebalance biochemical processes that facilitate survival and maintain their existence. Different kinds of stress stimuli trigger epigenetic alterations in cancer cells, which leads to changes in their transcriptome and metabolome, ultimately resulting in suppression of growth inhibition or induction of apoptosis. Whether cancer cells show a protective response to stress or succumb to cell death depends on the type of stress and duration of exposure. A thorough understanding of epigenetic and molecular architecture of cancer cell stress response pathways can unveil a plethora of information required to develop novel anti-cancer therapeutics. The present view highlights current knowledge about alterations in epigenome and transcriptome of cancer cells as a consequence of exposure to different physicochemical stressful stimuli such as reactive oxygen species (ROS), hypoxia, radiation, hyperthermia, genotoxic agents, and nutrient deprivation. Currently, an anti-cancer treatment scenario involving the imposition of stress on target cancer cells is gaining traction to augment or even replace conventional therapeutic regimens. Therefore, a comprehensive understanding of stress response pathways is crucial for devising and implementing novel therapeutic strategies.

scholarly journals Hampering Stromal Cells in the Tumor Microenvironment as a Therapeutic Strategy to Destem Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3191
Author(s):  
Katherine Po Sin Chung ◽  
Rainbow Wing Hei Leung ◽  
Terence Kin Wah Lee
Keyword(s):  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Current Knowledge ◽  
Special Focus ◽  
Intrinsic Regulation ◽  
Mechanistic Basis ◽  
Novel Therapeutic Strategies

Cancer stem cells (CSCs) within the tumor bulk play crucial roles in tumor initiation, recurrence and therapeutic resistance. In addition to intrinsic regulation, a growing body of evidence suggests that the phenotypes of CSCs are also regulated extrinsically by stromal cells in the tumor microenvironment (TME). Here, we discuss the current knowledge of the interplay between stromal cells and cancer cells with a special focus on how stromal cells drive the stemness of cancer cells and immune evasive mechanisms of CSCs. Knowledge gained from the interaction between CSCs and stromal cells will provide a mechanistic basis for the development of novel therapeutic strategies for the treatment of cancers.

scholarly journals Hydrogen Sulfide Signaling Axis as a Target for Prostate Cancer Therapeutics

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Mingzhe Liu ◽  
Lingyun Wu ◽  
Sabine Montaut ◽  
Guangdong Yang
Keyword(s):  
Prostate Cancer ◽  
Hydrogen Sulfide ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Cancer Therapeutics ◽  
The Body ◽  
Health Concern ◽  
Diallyl Disulfide ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells

Hydrogen sulfide (H2S) was originally considered toxic at elevated levels; however just in the past decade H2S has been proposed to be an important gasotransmitter with various physiological and pathophysiological roles in the body. H2S can be generated endogenously from L-cysteine by multiple enzymes, including cystathionine gamma-lyase, cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase in combination with cysteine aminotransferase. Prostate cancer is a major health concern and no effective treatment for prostate cancers is available. H2S has been shown to inhibit cell survival of androgen-independent, androgen-dependent, and antiandrogen-resistant prostate cancer cells through different mechanisms. Various H2S-releasing compounds, including sulfide salts, diallyl disulfide, diallyl trisulfide, sulforaphane, and other polysulfides, also have been shown to inhibit prostate cancer growth and metastasis. The expression of H2S-producing enzyme was reduced in both human prostate cancer tissues and prostate cancer cells. Androgen receptor (AR) signaling is indispensable for the development of castration resistant prostate cancer, and H2S was shown to inhibit AR transactivation and contributes to antiandrogen-resistant status. In this review, we summarized the current knowledge of H2S signaling in prostate cancer and described the molecular alterations, which may bring this gasotransmitter into the clinic in the near future for developing novel pharmacological and therapeutic interventions for prostate cancer.

scholarly journals Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

2020 ◽  
Vol 9 (10) ◽  
pp. 3226
Author(s):  
Cristina Belgiovine ◽  
Elisabeth Digifico ◽  
Clément Anfray ◽  
Aldo Ummarino ◽  
Fernando Torres Andón
Keyword(s):  
Current Knowledge ◽  
Cancer Therapies ◽  
Combination Therapies ◽  
Tumor Associated Macrophages ◽  
Effector Cells ◽  
Anti Cancer ◽  
Novel Therapeutic Strategies ◽  
The Right ◽  
Do The Right Thing ◽  
Cytotoxic Effector

In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapies.

scholarly journals Therapeutic Perspectives of Molecules from Urtica dioica Extracts for Cancer Treatment

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2753 ◽  
Author(s):  
Sabrina Esposito ◽  
Alessandro Bianco ◽  
Rosita Russo ◽  
Antimo Di Maro ◽  
Carla Isernia ◽  
...  
Keyword(s):  
Natural Products ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Biological Activities ◽  
Urtica Dioica ◽  
Cancer Therapies ◽  
Edible Plant ◽  
Bioactive Natural Products ◽  
Human Cancers ◽  
Anti Cancer

A large range of chronic and degenerative diseases can be prevented through the use of food products and food bioactives. This study reports the health benefits and biological activities of the Urtica dioica (U. dioica) edible plant, with particular focus on its cancer chemopreventive potential. Numerous studies have attempted to investigate the most efficient anti-cancer therapy with few side effects and high toxicity on cancer cells to overcome the chemoresistance of cancer cells and the adverse effects of current therapies. In this regard, natural products from edible plants have been assessed as sources of anti-cancer agents. In this article, we review current knowledge from studies that have examined the cytotoxic, anti-tumor and anti-metastatic effects of U. dioica plant on several human cancers. Special attention has been dedicated to the treatment of breast cancer, the most prevalent cancer among women and one of the main causes of death worldwide. The anti-proliferative and apoptotic effects of U. dioica have been demonstrated on different human cancers, investigating the properties of U. dioica at cellular and molecular levels. The potent cytotoxicity and anti-cancer activity of the U. dioica extracts are due to its bioactive natural products content, including polyphenols which reportedly possess anti-oxidant, anti-mutagenic and anti-proliferative properties. The efficacy of this edible plant to prevent or mitigate human cancers has been demonstrated in laboratory conditions as well as in experimental animal models, paving the way to the development of nutraceuticals for new anti-cancer therapies.

Effects of a Novel Histone Deacetylase Inhibitor, PXD101, When Used as Monotherapy or in Combination with Bortezomib on Tumor Growth in Mouse Models of Human Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3483-3483 ◽  
Author(s):  
Richard A. Campbell ◽  
Eric Sanchez ◽  
Haiming Chen ◽  
Lauren Turker ◽  
Olivia Trac ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Mouse Models ◽  
Optimal Schedule ◽  
Cancer Therapeutics ◽  
Mouse Serum ◽  
Wide Range ◽  
Anti Cancer ◽  
Human Multiple Myeloma

Abstract Histone deacetylase (HDAC) inhibitors represent a new mechanistic class of anti-cancer therapeutics that inhibit HDAC enzymes and have been shown to have anti-proliferative effects in cancer cells (including drug resistance subtypes), induce apoptosis, inhibit angiogenesis, and sensitize cancer cells when combined with other available anti-cancer therapies. PXD101 is a novel investigational small molecule drug that selectively inhibits HDAC enzymes. In recent preclinical studies, PXD101 has been shown to have the potential to treat a wide range of solid and hematological malignancies either as a monotherapy or in combination with other active agents. In this study, we evaluated the activity of PXD101 on multiple myeloma samples when used as monotherapy or in combination with the proteasome inhibitor bortezomib. In vitro experiments indicated that PXD101 pretreatment (20 mM; 3h) sensitized RPMI-8226 human multiple myeloma cells to subsequent bortezomib exposure (5 nM; 72h). To examine PXD101 and bortezomib in vivo, two mouse models of human multiple myeloma were utilized (LAGλ-1 and LAGκ-1B). LAGλ-1 was generated from a patient resistant to melphalan therapy and LAGκ-1B from a patient who progressed on bortezomib treatment (Campbell et al, International Journal of Oncology 2006). SCID mice were implanted with LAGλ-1 or LAGκ-1B tumor fragments into the left superficial gluteal muscle. Tumors were allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum, and mice were randomly assigned into treatment groups. Groups consisted of Vehicle only, PXD101 alone (40 mg/kg), bortezomib alone (0.5 mg/kg), or PXD101 (40 mg/kg) + bortezomib (0.5 mg/kg). In one cohort, PXD101 and bortezomib were administered twice weekly (M, Th) and in another cohort PXD101 was administered 5 days a week (M-F) and bortezomib twice weekly (M, Th). When administered, PXD101 was given i.p twice daily and bortezomib once daily intravenously. The results of these animal experiments will provide preclinical information on the activity of PXD101 monotherapy and PXD101/bortezomib combination therapy on drug-resistant myeloma samples, and may help to define the optimal schedule for potential clinical evaluation of this drug combination.

scholarly journals Antagonistic effects of chemical mixtures on the oxidative stress response are silenced by heat stress and reversed under dietary restriction

Exposome ◽  
2021 ◽  
Author(s):  
Karthik Suresh Arulalan ◽  
Javier Huayta ◽  
Jonathan W Stallrich ◽  
Adriana San-Miguel
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Design Of Experiments ◽  
Stress Responses ◽  
Current Knowledge ◽  
Oxidative Stress Response ◽  
Chemical Mixtures ◽  
C Elegans ◽  
Chemical Agents ◽  
Limited Food

Abstract Chemical agents released into the environment can induce oxidative stress in organisms, which is detrimental for health. Although environmental exposures typically include multiple chemicals, organismal studies on oxidative stress derived from chemical agents commonly study exposures to individual compounds. In this work, we explore how chemical mixtures drive the oxidative stress response under various conditions in the nematode C. elegans, by quantitatively assessing levels of gst-4 expression. Our results indicate that naphthoquinone mixtures drive responses differently than individual components, and that altering environmental conditions, such as increased heat and reduced food availability, result in dramatically different oxidative stress responses mounted by C. elegans. When exposed to heat, the oxidative stress response is diminished. Notably, when exposed to limited food, the oxidative stress response specific to juglone is significantly heightened, while identified antagonistic interactions between some naphthoquinone components in mixtures are abolished. This implies that organismal responses to xenobiotics is confounded by environment and stressor interactions. Given the high number of variables under study, and their potential combinations, a simplex centroid design was used to capture such non-trivial response over the design space. This makes the case for the adoption of Design of Experiments approaches as they can greatly expand the experimental space probed in noisy biological readouts, and in combinatorial experiments. Our results also reveal gaps in our current knowledge of the organismal oxidative stress response, which can be addressed by employing sophisticated design of experiments approaches to identify significant interactions.

scholarly journals Brassicaceae-Derived Anticancer Agents: Towards a Green Approach to Beat Cancer

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 868 ◽  
Author(s):  
Luigi Mandrich ◽  
Emilia Caputo
Keyword(s):  
Anticancer Agents ◽  
Current Knowledge ◽  
Cancer Therapeutics ◽  
Cancer Treatments ◽  
Mortality And Morbidity ◽  
Green Approach ◽  
Anti Cancer ◽  
Brassica Vegetables ◽  
Health Promoting ◽  
Domestic Processing

Cancer is the main cause of mortality and morbidity worldwide. Although a large variety of therapeutic approaches have been developed and translated into clinical protocols, the toxic side effects of cancer treatments negatively impact patients, allowing cancer to grow. Brassica metabolites are emerging as new weapons for anti-cancer therapeutics. The beneficial role of the consumption of brassica vegetables, the most-used vegetables in the Mediterranean diet, particularly broccoli, in the prevention of chronic diseases, including cardiovascular diseases, diabetes, and obesity, has been well-documented. In this review, we discuss the anti-tumor effects of the bioactive compounds from Brassica vegetables with regard to the compounds and types of cancer against which they show activity, providing current knowledge on the anti-cancer effects of Brassica metabolites against major types of tumors. In addition, we discuss the impacts of industrial and domestic processing on the compounds’ functional properties before their consumption as well as the main strategies used to increase the content of health-promoting metabolites in Brassica plants through biofortification. Finally, the impacts of microbiota on the compounds’ bioactivity are considered. This information will be helpful for the further development of efficacious anti-cancer drugs.

scholarly journals Synthesis of a hemoglobin-conjugated triblock copolymer for oxygen carrying and specific recognition of cancer cells

RSC Advances ◽  
2017 ◽  
Vol 7 (76) ◽  
pp. 48166-48175 ◽  
Author(s):  
Huixuan Bu ◽  
Xin Xu ◽  
Jiaming Chen ◽  
Yuecheng Cui ◽  
Li-Qun Wang
Keyword(s):  
Cancer Cells ◽  
Triblock Copolymer ◽  
Cancer Therapeutics ◽  
Specific Recognition ◽  
Anti Cancer

Considering that hypoxia causes resistance to anti-cancer therapeutics, we synthesized a hemoglobin-based nanocarrier for oxygen carrying and recognition of cancer cells.

scholarly journals Opportunities for Ferroptosis in Cancer Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 986
Author(s):  
Kenji M. Fujihara ◽  
Bonnie Z. Zhang ◽  
Nicholas J. Clemons
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Cancer Therapeutics ◽  
Therapeutic Window ◽  
Anti Cancer

A critical hallmark of cancer cells is their ability to evade programmed apoptotic cell death. Consequently, resistance to anti-cancer therapeutics is a hurdle often observed in the clinic. Ferroptosis, a non-apoptotic form of cell death distinguished by toxic lipid peroxidation and iron accumulation, has garnered substantial attention as an alternative therapeutic strategy to selectively destroy tumours. Although there is a plethora of research outlining the molecular mechanisms of ferroptosis, these findings are yet to be translated into clinical compounds inducing ferroptosis. In this perspective, we elaborate on how ferroptosis can be leveraged in the clinic. We discuss a therapeutic window for compounds inducing ferroptosis, the subset of tumour types that are most sensitive to ferroptosis, conventional therapeutics that induce ferroptosis, and potential strategies for lowering the threshold for ferroptosis.

scholarly journals Specific Antiproliferative Properties of Proteinaceous Toxin Secretions from the Marine Annelid Eulalia sp. onto Ovarian Cancer Cells

Marine Drugs ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. 31 ◽  
Author(s):  
Ana P. Rodrigo ◽  
Vera M. Mendes ◽  
Bruno Manadas ◽  
Ana R. Grosso ◽  
António P. Alves de Matos ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cancer Therapeutics ◽  
Fine Tuning ◽  
Ovarian Cancer Cells ◽  
Cycle Arrest ◽  
Arylsulfatase B ◽  
Anti Cancer

As Yondelis joins the ranks of approved anti-cancer drugs, the benefit from exploring the oceans’ biodiversity becomes clear. From marine toxins, relevant bioproducts can be obtained due to their potential to interfere with specific pathways. We explored the cytotoxicity of toxin-bearing secretions of the polychaete Eulalia onto a battery of normal and cancer human cell lines and discovered that the cocktail of proteins is more toxic towards an ovarian cancer cell line (A2780). The secretions’ main proteins were identified by proteomics and transcriptomics: 14-3-3 protein, Hsp70, Rab3, Arylsulfatase B and serine protease, the latter two being known toxins. This mixture of toxins induces cell-cycle arrest at G2/M phase after 3h exposure in A2780 cells and extrinsic programmed cell death. These findings indicate that partial re-activation of the G2/M checkpoint, which is inactivated in many cancer cells, can be partly reversed by the toxic mixture. Protein–protein interaction networks partake in two cytotoxic effects: cell-cycle arrest with a link to RAB3C and RAF1; and lytic activity of arylsulfatases. The discovery of both mechanisms indicates that venomous mixtures may affect proliferating cells in a specific manner, highlighting the cocktails’ potential in the fine-tuning of anti-cancer therapeutics targeting cell cycle and protein homeostasis.

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