Resveratrol as an Adjuvant for Normal Tissues Protection and Tumor Sensitization

2020 ◽  
Vol 20 (2) ◽  
pp. 130-145 ◽  
Author(s):  
Keywan Mortezaee ◽  
Masoud Najafi ◽  
Bagher Farhood ◽  
Amirhossein Ahmadi ◽  
Dheyauldeen Shabeeb ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Clinical Studies ◽  
Normal Tissue ◽  
Medical Science ◽  
Treatment Modalities ◽  
Radiation Toxicity ◽  
Normal Tissues ◽  
Normal Tissue Toxicity

Cancer is one of the most complicated diseases in present-day medical science. Yearly, several studies suggest various strategies for preventing carcinogenesis. Furthermore, experiments for the treatment of cancer with low side effects are ongoing. Chemotherapy, targeted therapy, radiotherapy and immunotherapy are the most common non-invasive strategies for cancer treatment. One of the most challenging issues encountered with these modalities is low effectiveness, as well as normal tissue toxicity for chemo-radiation therapy. The use of some agents as adjuvants has been suggested to improve tumor responses and also alleviate normal tissue toxicity. Resveratrol, a natural flavonoid, has attracted a lot of attention for the management of both tumor and normal tissue responses to various modalities of cancer therapy. As an antioxidant and anti-inflammatory agent, in vitro and in vivo studies show that it is able to mitigate chemo-radiation toxicity in normal tissues. However, clinical studies to confirm the usage of resveratrol as a chemo-radioprotector are lacking. In addition, it can sensitize various types of cancer cells to both chemotherapy drugs and radiation. In recent years, some clinical studies suggested that resveratrol may have an effect on inducing cancer cell killing. Yet, clinical translation of resveratrol has not yielded desirable results for the combination of resveratrol with radiotherapy, targeted therapy or immunotherapy. In this paper, we review the potential role of resveratrol for preserving normal tissues and sensitization of cancer cells in combination with different cancer treatment modalities.

scholarly journals Auger electrons for cancer therapy – a review

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Anthony Ku ◽  
Valerie J. Facca ◽  
Zhongli Cai ◽  
Raymond M. Reilly
Keyword(s):  
Cancer Treatment ◽  
Cancer Cells ◽  
Clinical Studies ◽  
Normal Tissue ◽  
Radiation Dosimetry ◽  
Bystander Effect ◽  
Water Radiolysis ◽  
Organ Doses ◽  
Auger Electrons ◽  
Normal Tissue Toxicity

Abstract Background Auger electrons (AEs) are very low energy electrons that are emitted by radionuclides that decay by electron capture (e.g. 111In, 67Ga, 99mTc, 195mPt, 125I and 123I). This energy is deposited over nanometre-micrometre distances, resulting in high linear energy transfer (LET) that is potent for causing lethal damage in cancer cells. Thus, AE-emitting radiotherapeutic agents have great potential for treatment of cancer. In this review, we describe the radiobiological properties of AEs, their radiation dosimetry, radiolabelling methods, and preclinical and clinical studies that have been performed to investigate AEs for cancer treatment. Results AEs are most lethal to cancer cells when emitted near the cell nucleus and especially when incorporated into DNA (e.g. 125I-IUdR). AEs cause DNA damage both directly and indirectly via water radiolysis. AEs can also kill targeted cancer cells by damaging the cell membrane, and kill non-targeted cells through a cross-dose or bystander effect. The radiation dosimetry of AEs considers both organ doses and cellular doses. The Medical Internal Radiation Dose (MIRD) schema may be applied. Radiolabelling methods for complexing AE-emitters to biomolecules (antibodies and peptides) and nanoparticles include radioiodination (125I and 123I) or radiometal chelation (111In, 67Ga, 99mTc). Cancer cells exposed in vitro to AE-emitting radiotherapeutic agents exhibit decreased clonogenic survival correlated at least in part with unrepaired DNA double-strand breaks (DSBs) detected by immunofluorescence for γH2AX, and chromosomal aberrations. Preclinical studies of AE-emitting radiotherapeutic agents have shown strong tumour growth inhibition in vivo in tumour xenograft mouse models. Minimal normal tissue toxicity was found due to the restricted toxicity of AEs mostly on tumour cells targeted by the radiotherapeutic agents. Clinical studies of AEs for cancer treatment have been limited but some encouraging results were obtained in early studies using 111In-DTPA-octreotide and 125I-IUdR, in which tumour remissions were achieved in several patients at administered amounts that caused low normal tissue toxicity, as well as promising improvements in the survival of glioblastoma patients with 125I-mAb 425, with minimal normal tissue toxicity. Conclusions Proof-of-principle for AE radiotherapy of cancer has been shown preclinically, and clinically in a limited number of studies. The recent introduction of many biologically-targeted therapies for cancer creates new opportunities to design novel AE-emitting agents for cancer treatment. Pierre Auger did not conceive of the application of AEs for targeted cancer treatment, but this is a tremendously exciting future that we and many other scientists in this field envision.

scholarly journals BCN057, a Modulator of GSK3b Induces KRAS G12D Mutant Pancreatic Cancer Cell Death

2021 ◽  
Author(s):  
Elizabeth M Singer ◽  
Rishi Mann Chugh ◽  
Payel Bhanja ◽  
Adrian Gomez ◽  
Lucy Gao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Normal Tissue ◽  
Synthetic Lethality ◽  
Human Pancreatic Cancer ◽  
Oncogenic Ras ◽  
Cancer Cell Death ◽  
Pancreatic Cancer Cells ◽  
Normal Tissue Toxicity

Effective treatment for Pancreatic Cancer remains a major challenge due to its resistance to radiation/chemotherapy and poor drug permeability. Moreover, treatment induced normal tissue toxicity, mainly to the duodenum and gastrointestinal epithelium, is common and is a dose limiting event, while toxicity to the pancreas is relatively rare. Gastrointestinal toxicity, however, often results in interruption, reduction or premature withdrawal of anti–cancer therapy which is a very significant factor impacting the overall survival of patients being treated. Therefore, development of a therapeutic strategy to selectively sensitize tumor tissue without inducing normal tissue toxicity is important. In this manuscript, we show that the novel small molecule BCN057 can modulate chemo–sensitivity of oncogenic RAS pancreatic cancer cells while conversely protecting normal intestinal epithelium from off target toxicity. In particular, BCN 057 protects Lgr5 positive intestinal stem cells, thereby preserving barrier function. Further, it is demonstrated that BCN057 inhibits GSK3β and thereby induces a pro apoptotic phosphorylation pattern on c–Jun in KRAS G12D mutant pancreatic cancer cells (Panc1) leading to the restoration of PTEN expression and consequent apoptosis. This appears to be a new mechanistic observation for the oncogenic RAS phenotype. Lastly, concurrent with its GSK3β inhibition, BCN057 is a small molecule inhibitor of PD–1 expression on human T–lymphocytes co cultured with human pancreatic cancer cells. In summary, BCN057 can promote synthetic lethality specifically to malignant cells and therefore should be considered to improve the therapeutic ratio in pancreatic and epithelial cancer treatment in conjunction with chemotherapy and radiation.

NADPH Oxidase as a Target for Modulation of Radiation Response; Implications to Carcinogenesis and Radiotherapy

2019 ◽  
Vol 12 (1) ◽  
pp. 50-60 ◽  
Author(s):  
Keywan Mortezaee ◽  
Nasser Hashemi Goradel ◽  
Peyman Amini ◽  
Dheyauldeen Shabeeb ◽  
Ahmed Eleojo Musa ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Nadph Oxidase ◽  
Tumor Cells ◽  
Normal Tissue ◽  
Therapeutic Effects ◽  
Radiation Toxicity ◽  
Ros Production ◽  
Normal Tissues ◽  
Increased Risk ◽  
Stimulation Of

Background:Radiotherapy is a treatment modality for cancer. For better therapeutic efficiency, it could be used in combination with surgery, chemotherapy or immunotherapy. In addition to its beneficial therapeutic effects, exposure to radiation leads to several toxic effects on normal tissues. Also, it may induce some changes in genomic expression of tumor cells, thereby increasing the resistance of tumor cells. These changes lead to the appearance of some acute reactions in irradiated organs, increased risk of carcinogenesis, and reduction in the therapeutic effect of radiotherapy.Discussion:So far, several studies have proposed different targets such as cyclooxygenase-2 (COX-2), some toll-like receptors (TLRs), mitogen-activated protein kinases (MAPKs) etc., for the amelioration of radiation toxicity and enhancing tumor response. NADPH oxidase includes five NOX and two dual oxidases (DUOX1 and DUOX2) subfamilies that through the production of superoxide and hydrogen peroxide, play key roles in oxidative stress and several signaling pathways involved in early and late effects of ionizing radiation. Chronic ROS production by NOX enzymes can induce genomic instability, thereby increasing the risk of carcinogenesis. Also, these enzymes are able to induce cell death, especially through apoptosis and senescence that may affect tissue function. ROS-derived NADPH oxidase causes apoptosis in some organs such as intestine and tongue, which mediate inflammation. Furthermore, continuous ROS production stimulates fibrosis via stimulation of fibroblast differentiation and collagen deposition. Evidence has shown that in contrast to normal tissues, the NOX system induces tumor resistance to radiotherapy through some mechanisms such as induction of hypoxia, stimulation of proliferation, and activation of macrophages. However, there are some contradictory results. Inhibition of NADPH oxidase in experimental studies has shown promising results for both normal tissue protection and tumor sensitization to ionizing radiation.Conclusion:In this article, we aimed to review the role of different subfamilies of NADPH oxidase in radiation-induced early and late normal tissue toxicities in different organs.

scholarly journals Molecular markers for prediction of risk of radiation-related injury to normal tissue

2010 ◽  
Vol 1 (1) ◽  
pp. 11 ◽  
Author(s):  
Marco Ghilotti ◽  
Marco Alessandro Pierotti ◽  
Manuela Gariboldi
Keyword(s):  
Ionizing Radiation ◽  
Normal Tissue ◽  
Target Genes ◽  
Expression Profiles ◽  
Association Studies ◽  
Gene Expression Profiles ◽  
Severe Reaction ◽  
Normal Tissues ◽  
Normal Tissue Toxicity ◽  
Radiation Genetic

Radiotherapy is one of the most effective methods for the treatment of cancer, but occurrence of adverse reactions developing in the co-irradiated normal tissue can be a threat for patients. Identification of individuals at risk of severe reaction is very difficult and considerable efforts have been made to correlate normal tissue toxicity with cellular responses to ionizing radiation. Genetic markers enabling to identify hyper-sensitive patients prior to treatment would considerably improve its outcome. Gene association studies should help to identify such markers. Expression levels of specific transcripts could be putative markers; in fact different studies found associations between gene expression profiles in normal cells and the reaction of normal tissues to radiation therapy. The finding that ionizing radiation induces the deregulation of a high number of genes suggests that also microRNAs that affect the expression of a large number of target genes may be involved. This review briefly introduces the mechanisms of radiation-induced normal tissue toxicity and summarizes clinical research focused on the evaluation of molecular biomarkers for predicting risk of injury to normal tissue, mainly describing gene transcripts alterations.

The unpaved journey of vitamin C in cancer treatment

2015 ◽  
Vol 93 (12) ◽  
pp. 1055-1063 ◽  
Author(s):  
Qi Chen ◽  
Kishore Polireddy ◽  
Ping Chen ◽  
Ruochen Dong
Keyword(s):  
Vitamin C ◽  
Alternative Medicine ◽  
Cancer Treatment ◽  
Complementary And Alternative Medicine ◽  
Clinical Studies ◽  
Therapeutic Strategy ◽  
Scientific Basis ◽  
Mechanisms Of Action ◽  
Normal Tissues ◽  
Low Toxicity

Effectiveness and low-toxicity to normal tissues are ideal properties for a cancer treatment, and one that numerous research programs are aiming for. Vitamin C has long been used in the field of Complementary and Alternative Medicine as a cancer treatment, with profound safety and anecdotal efficacy. Recent studies revealed the scientific basis for this use, and indicated that vitamin C, at supra-nutritional doses, holds considerable promise as an effective and low-toxic therapeutic strategy to treat cancer. Reviewed here are the early controversies surrounding vitamin C and cancer treatment, the breakthrough discoveries that led to the current advancement, and recent clinical studies, as well as research into its mechanisms of action.

scholarly journals Cancer Treatment Based on the Selective Accumulation of a Photosensitiser and Laser Light Irradiation: A Review

2021 ◽  
Vol 46 (3) ◽  
pp. 150-153
Author(s):  
Zahra Al Timimi
Keyword(s):  
Cancer Treatment ◽  
Cancer Cells ◽  
Laser Light ◽  
Active Form ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Treatment Quality ◽  
Laser Source ◽  
Normal Tissues ◽  
Selective Accumulation

Background: Cancer Photodynamic Therapy (CPDT) is a promising future treatment quality based on the selective accumulation of a photosensitiser in the malignant tissues and the dependent irradiation with laser light. Objective: The aim of this work was to estimate an optimum effect involves the performance of a photosensitizing agent served by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the appearance of oxygen, a series of effects lead to direct tumour cell death and damage to the microvasculature and initiation of a local inflammatory reaction. Methods: Photosensitiser is a material that sensitizes an organism, cell, or tissue to the light. It is a deeprooted part of CPDT, which absorbed by cancerous cells and exposed to laser light, gets activated, damaging and killing cancer cells. The direct targeting of laser source on hyper proliferative tissue and its preferential origin absorption at the targeted site gives rise CPDT double selectivity with least damage to adjacent normal tissues. Results: Photosensitiser absorbs the light and then produces an active form of oxygen, which destroys nearby cancer cells. The photosensitiser is able to spoil the blood vessels in the tumour, that way preventing cancer from receiving any necessary nutrients. The light which needed to activate most of the photosensitisers cannot pass through more than about one-third of an inch of tissue, because of that reason, the CPDT is usually used to treat cancer on or just under the skin or on the lining of internal organs. In addition, CPDT may activate the immune system to attack the tumour cells, directly killing cancer cells. Conclusion: This review focuses on the aspects of CPDT as an advanced and original site directed therapy for cancer treatment and the other non-oncogenic diseases. Minimal average of tissue toxicity controlled a long-term morbidity, deficiency of intrinsic or acquired resistance mechanisms. Bangladesh Med Res Counc Bull 2020; 46(3): 150-153

CANCER INSIGHT: HALLMARKS AND THERAPEUTIC STRATEGIES

2021 ◽  
Vol 5 (1) ◽  
pp. 4-5
Author(s):  
Muhammad Sulaiman Yousafzai
Keyword(s):  
Radiation Therapy ◽  
Targeted Therapy ◽  
Cancer Cells ◽  
Cell Biology ◽  
Cancer Metastasis ◽  
Cytotoxic Agents ◽  
Host Cells ◽  
External Beam Radiation ◽  
Treatment Modalities ◽  
Beam Radiation

Cancer metastasis is a complex, multistep process responsible for > 90% of cancer-related deaths. Cancer is the second leading cause of death globally and about 8.8 million people worldwide died from cancer (Liver (788 000), Lung (1.69 million) Colorectal (774 000), Stomach (754 000), Breast (571 000)) in 20151. That is nearly 1 in 6 of all global deaths. Lung, prostate, colorectal, stomach and liver cancer are the most common types of cancer in men, while breast, colorectal, lung, cervix and stomach cancer are the most common among women. During metastasis, the primary tumor seeds pioneer cells that move out, invade adjacent tissues, and then travel to distant sites where they may succeed in founding new colonies called secondary tumors . In the last few decades, a rich and complex body of knowledge has been generated in cancer, revealing cancer to be a disease involving dynamic changes in the genome. In 2000, Douglas Hanahan and Robert A. Weinberg reported six hallmarks of cancer. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation. Cancer Initiation, detachment and organ-specific affinity of cancer cells to host cells in terms of the above mentioned hallmarks helped devise new potential therapies. To date, five cancer treatment modalities have been defined. Currently available cancer treatments include the traditional surgery (Cryosurgery, Lasers,Hyperthermia), radiotherapy (External Beam Radiation Therapy, Internal Radiation Therapy), and conventional chemotherapy (Oral, Intravenous (IV), Injection, Intrathecal, Intraperitoneal (IP), Intraarterial (IA), Topical), approaches and have been extended with two new modalities in recent decades: molecularly targeted therapy (MTT) ( Small -molecule drugs, antibodies ) and immunotherapy Monoclonal antibodies,, Adoptive cell transfer, Cytokines, Treatment Vaccines, Bacillus Calmette-Guérin (BCG)). The most important goal of targeted therapy or more advanced immune-based strategies is to eradicate cancer cells more specifically than traditional theraphies while maintaining an acceptable level of side effects and quality of life. Unfortunately, the newly developed targeted agents or techniques show a similar incidence and severity of toxicities as traditional cytotoxic agents do. With a full clarity of mechanism, cancer prognosis  and treatment will become a rational science. It's a dream that one day the patchwork quilt of major fields like cell biology, genetics, histopathology, biochemistry, immunology, pharmacology and physics will detect and identify all stages of cancer progression and will be able to prevent incipient cancers from developing and will cure preexisting cancers.

Strahlenwirkung am Normalgewebe

2010 ◽  
Vol 49 (S 01) ◽  
pp. S53-S58 ◽  
Author(s):  
W. Dörr
Keyword(s):  
Radiation Exposure ◽  
Normal Tissue ◽  
Radiation Effects ◽  
A Priori ◽  
Cell Loss ◽  
Turnover Time ◽  
Complete Healing ◽  
Internal Radiotherapy ◽  
Normal Tissues ◽  
Chronic Radiation

SummaryThe curative effectivity of external or internal radiotherapy necessitates exposure of normal tissues with significant radiation doses, and hence must be associated with an accepted rate of side effects. These complications can not a priori be considered as an indication of a too aggressive therapy. Based on the time of first diagnosis, early (acute) and late (chronic) radiation sequelae in normal tissues can be distinguished. Early reactions per definition occur within 90 days after onset of the radiation exposure. They are based on impairment of cell production in turnover tissues, which in face of ongoing cell loss results in hypoplasia and eventually a complete loss of functional cells. The latent time is largely independent of dose and is defined by tissue biology (turnover time). Usually, complete healing of early reactions is observed. Late radiation effects can occur after symptom-free latent times of months to many years, with an inverse dependence of latency on dose. Late normal tissue changes are progressive and usually irreversible. They are based on a complex interaction of damage to various cell populations (organ parenchyma, connective tissue, capillaries), with a contribution from macrophages. Late effects are sensitive for a reduction in dose rate (recovery effects).A number of biologically based strategies for protection of normal tissues or for amelioration of radiation effects was and still is tested in experimental systems, yet, only a small fraction of these approaches has so far been introduced into clinical studies. One advantage of most of the methods is that they may be effective even if the treatment starts way after the end of radiation exposure. For a clinical exploitation, hence, the availability of early indicators for the progression of subclinical damage in the individual patient would be desirable. Moreover, there is need to further investigate the molecular pathogenesis of normal tissue effects in more detail, in order to optimise biology based preventive strategies, as well as to identify the precise mechanisms of already tested approaches (e. g. stem cells).

NOB1: A Potential Biomarker or Target in Cancer

2019 ◽  
Vol 20 (10) ◽  
pp. 1081-1089
Author(s):  
Weiwei Ke ◽  
Zaiming Lu ◽  
Xiangxuan Zhao
Keyword(s):  
Cancer Treatment ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Binding Protein ◽  
Tumor Development ◽  
Anticancer Therapy ◽  
Research Progress ◽  
Normal Tissues ◽  
Potential Biomarker

Human NIN1/RPN12 binding protein 1 homolog (NOB1), an RNA binding protein, is expressed ubiquitously in normal tissues such as the lung, liver, and spleen. Its core physiological function is to regulate protease activities and participate in maintaining RNA metabolism and stability. NOB1 is overexpressed in a variety of cancers, including pancreatic cancer, non-small cell lung cancer, ovarian cancer, prostate carcinoma, osteosarcoma, papillary thyroid carcinoma, colorectal cancer, and glioma. Although existing data indicate that NOB1 overexpression is associated with cancer growth, invasion, and poor prognosis, the molecular mechanisms behind these effects and its exact roles remain unclear. Several studies have confirmed that NOB1 is clinically relevant in different cancers, and further research at the molecular level will help evaluate the role of NOB1 in tumors. NOB1 has become an attractive target in anticancer therapy because it is overexpressed in many cancers and mediates different stages of tumor development. Elucidating the role of NOB1 in different signaling pathways as a potential cancer treatment will provide new ideas for existing cancer treatment methods. This review summarizes the research progress made into NOB1 in cancer in the past decade; this information provides valuable clues and theoretical guidance for future anticancer therapy by targeting NOB1.

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