Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property

“Let food be thy medicine and medicine be thy food” was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating) behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents.

Download Full-text

Anti-Cancer Activity of Porphyran and Carrageenan from Red Seaweeds

Molecules ◽

10.3390/molecules24234286 ◽

2019 ◽

Vol 24 (23) ◽

pp. 4286 ◽

Cited By ~ 15

Author(s):

Zhiwei Liu ◽

Tianheng Gao ◽

Ying Yang ◽

Fanxin Meng ◽

Fengping Zhan ◽

...

Keyword(s):

Bioactive Compounds ◽

Marine Environment ◽

Animal Health ◽

Natural Compounds ◽

Chemotherapeutic Agents ◽

Chemopreventive Agents ◽

Red Seaweeds ◽

Anti Cancer ◽

Cancer Activity

Seaweeds are some of the largest producers of biomass in the marine environment and are rich in bioactive compounds that are often used for human and animal health. Porphyran and carrageenan are natural compounds derived from red seaweeds. The former is a characteristic polysaccharide of Porphyra, while the latter is well known from Chondrus, Gigartina, and various Eucheuma species, all in Rhodophyceae. The two polysaccharides have been found to have anti-cancer activity by improving immunity and targeting key apoptotic molecules and therefore deemed as potential chemotherapeutic or chemopreventive agents. This review attempts to review the current study of anti-cancer activity and the possible mechanisms of porphyran and carrageenan derived from red seaweeds to various cancers, and their cooperative actions with other anti-cancer chemotherapeutic agents is also discussed.

Download Full-text

Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ42 Oligomers

10.26434/chemrxiv.12445505 ◽

2020 ◽

Author(s):

Liang Sun ◽

Anuj K. Sharma ◽

Byung-Hee Han ◽

Liviu M. Mirica

Keyword(s):

Reactive Oxygen Species ◽

Metal Ions ◽

Antioxidant Properties ◽

Reactive Oxygen ◽

Amyloid Plaques ◽

Transition Metal Ions ◽

Oxygen Species ◽

High Affinity ◽

Amyloid Aβ ◽

Β Amyloid

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet the cause and progression of this disorder are not completely understood. While the main hallmark of AD is the deposition of amyloid plaques consisting of the β-amyloid (Aβ) peptide, transition metal ions are also known to play a significant role in disease pathology by expediting the formation of neurotoxic soluble β-amyloid (Aβ) oligomers, reactive oxygen species (ROS), and oxidative stress. Thus, bifunctional metal chelators that can control these deleterious properties are highly desirable. Herein, we show that amentoflavone (AMF) – a natural biflavonoid compound, exhibits good metal-chelating properties, especially for chelating Cu2+ with very high affinity (pCu7.4 = 10.44). In addition, AMF binds to Aβ fibrils with a high affinity (Ki = 287 ± 20 nM) – as revealed by a competition thioflavin T (ThT) assay, and specifically labels the amyloid plaques ex vivo in the brain sections of transgenic AD mice – as confirmed via immunostaining with an Ab antibody. The effect of AMF on Aβ42 aggregation and disaggregation of Aβ42 fibrils was also investigated, to reveal that AMF can control the formation of neurotoxic soluble Aβ42 oligomers, both in absence and presence of metal ions, and as confirmed via cell toxicity studies. Furthermore, an ascorbate consumption assay shows that AMF exhibits potent antioxidant properties and can chelate Cu2+ and significantly diminish the Cu2+-ascorbate redox cycling and reactive oxygen species (ROS) formation. Overall, these studies strongly suggest that AMF acts as a bifunctional chelator that can interact with various Aβ aggregates and reduce their neurotoxicity, can also bind Cu2+ and mediate its deleterious redox properties, and thus AMF has the potential to be a lead compound for further therapeutic agent development for AD.

Download Full-text

CLytA-DAAO Chimeric Enzyme Bound to Magnetic Nanoparticles. A New Therapeutical Approach for Cancer Patients?

International Journal of Molecular Sciences ◽

10.3390/ijms22031477 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1477

Author(s):

María Fuentes-Baile ◽

Elizabeth Pérez-Valenciano ◽

Pilar García-Morales ◽

Camino de Juan Romero ◽

Daniel Bello-Gil ◽

...

Keyword(s):

Magnetic Nanoparticles ◽

Colorectal Carcinoma ◽

Acid Oxidase ◽

Oxygen Species ◽

Cell Models ◽

Amino Acid Oxidase ◽

Direct Addition ◽

Alginate Capsules ◽

Anti Cancer ◽

The Stability

D-amino acid oxidase (DAAO) is an enzyme that catalyzes the oxidation of D-amino acids generating H2O2. The enzymatic chimera formed by DAAO bound to the choline-binding domain of N-acetylmuramoyl-L-alanine amidase (CLytA) induces cytotoxicity in several pancreatic and colorectal carcinoma and glioblastoma cell models. In the current work, we determined whether the effect of CLytA-DAAO immobilized in magnetic nanoparticles, gold nanoparticles, and alginate capsules offered some advantages as compared to the free CLytA-DAAO. Results indicate that the immobilization of CLytA-DAAO in magnetic nanoparticles increases the stability of the enzyme, extending its time of action. Besides, we compared the effect induced by CLytA-DAAO with the direct addition of hydrogen peroxide, demonstrating that the progressive generation of reactive oxygen species by CLytA-DAAO is more effective in inducing cytotoxicity than the direct addition of H2O2. Furthermore, a pilot study has been initiated in biopsies obtained from pancreatic and colorectal carcinoma and glioblastoma patients to evaluate the expression of the main genes involved in resistance to CLytA-DAAO cytotoxicity. Based on our findings, we propose that CLytA-DAAO immobilized in magnetic nanoparticles could be effective in a high percentage of patients and, therefore, be used as an anti-cancer therapy for pancreatic and colorectal carcinoma and glioblastoma.

Download Full-text

Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice

Antioxidants ◽

10.3390/antiox10020163 ◽

2021 ◽

Vol 10 (2) ◽

pp. 163

Author(s):

Kristell Le Gal ◽

Clotilde Wiel ◽

Mohamed X. Ibrahim ◽

Marcus Henricsson ◽

Volkan I. Sayin ◽

...

Keyword(s):

Lung Cancer ◽

Malignant Melanoma ◽

Cancer Cells ◽

Cancer Progression ◽

Nuclear Dna ◽

Human Melanoma ◽

Oxygen Species ◽

Lung Cancer Cell ◽

Primary Tumors ◽

Anti Cancer

Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, we administered the mitochondria-targeted antioxidants MitoQ and MitoTEMPO to mice with BRAF-induced malignant melanoma and KRAS-induced lung cancer, and found that these compounds had no impact on the number of primary tumors and metastases; and did not influence mitochondrial and nuclear DNA damage levels. Moreover, MitoQ and MitoTEMPO did not influence proliferation of human melanoma and lung cancer cell lines. MitoQ and its control substance dTPP, but not MitoTEMPO, increased glycolytic rates and reduced respiration in melanoma cells; whereas only dTPP produced this effect in lung cancer cells. Our results do not support the use of mitochondria-targeted antioxidants for anti-cancer monotherapy, at least not in malignant melanoma and lung cancer.

Download Full-text

Cancer Prevention in Patients with GERD and Barrett’s Esophagus—Medicine

Foregut: The Journal of the American Foregut Society ◽

10.1177/2634516121993676 ◽

2021 ◽

Vol 1 (1) ◽

pp. 50-62

Author(s):

Carmelo Scarpignato ◽

David H. Wang

Keyword(s):

Risk Factors ◽

Reactive Oxygen Species ◽

Cell Proliferation ◽

Barrett’S Esophagus ◽

Barrett's Esophagus ◽

Acid Reflux ◽

Oxygen Species ◽

Esophageal Reflux ◽

Early Disease ◽

Chemopreventive Agents

Gastro-esophageal reflux disease (GERD) and Barrett’s esophagus are risk factors for esophageal adenocarcinoma (EAC). Chemoprevention is an attractive strategy, more effective than identifying early disease. Since acid reflux can lead to increased cell proliferation, decreased apoptosis, production of reactive oxygen species, DNA damage, and esophageal production of proinflammatory and pro-proliferative cytokines, proton pump inhibitors (PPIs) alone, or in combination with COX-inhibition, are the most suitable chemopreventive agents. Other compounds (statins, metformin, and selected nutraceuticals) cannot currently be recommended. Data are strong enough to warrant PPI treatment of virtually all patients with Barrett’s esophagus, although the best regimen has not yet been defined.

Download Full-text

Plant-Derived Anticancer Compounds as New Perspectives in Drug Discovery and Alternative Therapy

Molecules ◽

10.3390/molecules26041109 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1109

Author(s):

Cristina Adriana Dehelean ◽

Iasmina Marcovici ◽

Codruta Soica ◽

Marius Mioc ◽

Dorina Coricovac ◽

...

Keyword(s):

Targeted Delivery ◽

Alternative Therapy ◽

Natural Compounds ◽

Mechanisms Of Action ◽

Chemotherapeutic Agents ◽

Biologically Active ◽

Bioactive Molecules ◽

Multi Drug Resistance ◽

Chemopreventive Agents ◽

Pharmaceutical Agents

Despite the recent advances in the field of chemically synthetized pharmaceutical agents, nature remains the main supplier of bioactive molecules. The research of natural products is a valuable approach for the discovery and development of novel biologically active compounds possessing unique structures and mechanisms of action. Although their use belongs to the traditional treatment regimes, plant-derived compounds still cover a large portion of the current-day pharmaceutical agents. Their medical importance is well recognized in the field of oncology, especially as an alternative to the limitations of conventional chemotherapy (severe side effects and inefficacy due to the occurrence of multi-drug resistance). This review offers a comprehensive perspective of the first blockbuster chemotherapeutic agents of natural origin’s (e.g. taxol, vincristine, doxorubicin) mechanism of action using 3D representation. In addition is portrayed the step-by-step evolution from preclinical to clinical evaluation of the most recently studied natural compounds with potent antitumor activity (e.g. resveratrol, curcumin, betulinic acid, etc.) in terms of anticancer mechanisms of action and the possible indications as chemotherapeutic or chemopreventive agents and sensitizers. Finally, this review describes several efficient platforms for the encapsulation and targeted delivery of natural compounds in cancer treatment

Download Full-text

Evaluation of Dimer of Epicatechin from an Endophytic Fungus Curvularia australiensis FC2AP on Acute Toxicity Levels, Anti-Inflammatory and Anti-Cervical Cancer Activity in Animal Models

Molecules ◽

10.3390/molecules26030654 ◽

2021 ◽

Vol 26 (3) ◽

pp. 654

Author(s):

Vellingiri Manon Mani ◽

Arockiam Jeyasundar Parimala Gnana Soundari ◽

Balamuralikrishnan Balasubramanian ◽

Sungkwon Park ◽

Utthapon Issara ◽

...

Keyword(s):

Cervical Cancer ◽

Acute Toxicity ◽

Endophytic Fungus ◽

Lethal Dose ◽

Chemotherapeutic Agents ◽

Cancer Drug ◽

Dependent Manner ◽

Anti Cancer ◽

Albino Mice ◽

Anti Inflammatory

Cervical cancer, as the most frequent cancer in women globally and accounts almost 14% in India. It can be prevented or treated with vaccines, radiation, chemotherapy, and brachytherapy. The chemotherapeutic agents cause adverse post effects by the destruction of the neighboring normal cells or altering the properties of the cells. In order to reduce the severity of the side effects caused by the chemically synthesized therapeutic agents, the current research developed an anti-cancer agent dimer of epicatechin (DoE), a natural bioactive secondary metabolite (BSM) mediated from an endophytic fungus Curvularia australiensis FC2AP. The investigation has initiated with the evaluation of inhibiting the angiogenesis which is a main activity in metastasis, and it was assessed through Hen’s Egg Test on Chorio Allantoic Membrane (HET-CAM) test; the BSM inhibited the growth of blood vessels in the developing chick embryo. Further the DoE was evaluated for its acute toxicity levels in albino mice, whereas the survival dose was found to be 1250 mg/kg and the lethal dose was 1500 mg/kg body weight of albino mice; hematological, biochemical, and histopathological analyses were assessed. The anti-inflammatory responses of the DoE were evaluated in carrageenan induced Wistar rats and the reduction of inflammation occurred in a dose-dependent manner. By fixing the effective dose for anti-inflammation analysis, the DoE was taken for the anti-cervical cancer analysis in benzo (a) pyrene induced female Sprague-Dawley rats for 60 days trial. After the stipulated days, the rats were taken for hematological antioxidants, lipid peroxidation (LPO), member bound enzymes, cervical histopathological and carcinogenic markers analyses. The results specified that the DoE has the capability of reducing the tumor in an efficient way. This is the first report of flavonoid-DoE production from an endophytic fungus C. australiensis has the anticancer potentiality and it can be stated as anti-cancer drug.

Download Full-text

Herbal Medicine Goshajinkigan Prevents Paclitaxel-Induced Mechanical Allodynia without Impairing Antitumor Activity of Paclitaxel

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/849754 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 16

Author(s):

Muh. Akbar Bahar ◽

Tsugunobu Andoh ◽

Keisuke Ogura ◽

Yoshihiro Hayakawa ◽

Ikuo Saiki ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Herbal Medicine ◽

Tumor Growth ◽

Mechanical Allodynia ◽

Chemotherapeutic Agents ◽

Antitumor Action ◽

Effective Strategies ◽

Anti Cancer ◽

Mammary Fat Pad ◽

4T1 Cells

Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of commonly used chemotherapeutic agents. However, there are no effective strategies to treat the neuropathy. We examined whether Goshajinkigan, a herbal medicine, would prevent paclitaxel-induced allodynia without affecting the anticancer action in mice. Murine breast cancer 4T1 cells were inoculated into the mammary fat pad. Paclitaxel (10 and 20 mg/kg, intraperitoneal, alternate day from day 7 postinoculation) inhibited the tumor growth, and Goshajinkigan (1 g/kg, oral, daily from day 2 postinoculation) did not affect the antitumor action of paclitaxel. Mechanical allodynia developed in the inoculated region due to tumor growth and in the hind paw due to paclitaxel-induced neuropathy. Paclitaxel-induced allodynia was markedly prevented by Goshajinkigan, although tumor-associated allodynia was not inhibited by Goshajinkigan. These results suggest that Goshajinkigan prevents paclitaxel-induced peripheral neuropathy without interfering with the anti-cancer action of paclitaxel.

Download Full-text

Reactive Oxygen Species-Mediated Control of Mitochondrial Biogenesis

International Journal of Cell Biology ◽

10.1155/2012/403870 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 36

Author(s):

Edgar D. Yoboue ◽

Anne Devin

Keyword(s):

Oxidative Stress ◽

Mitochondrial Biogenesis ◽

Redox State ◽

Mitochondrial Genomes ◽

Oxygen Species ◽

Mitochondrial Content ◽

Cellular Redox ◽

High Importance ◽

Complex Process ◽

Long Time

Mitochondrial biogenesis is a complex process. It necessitates the contribution of both the nuclear and the mitochondrial genomes and therefore crosstalk between the nucleus and mitochondria. It is now well established that cellular mitochondrial content can vary according to a number of stimuli and physiological states in eukaryotes. The knowledge of the actors and signals regulating the mitochondrial biogenesis is thus of high importance. The cellular redox state has been considered for a long time as a key element in the regulation of various processes. In this paper, we report the involvement of the oxidative stress in the regulation of some actors of mitochondrial biogenesis.

Download Full-text

Probiotics for the Chemoprotective Role Against the Toxic Effect of Cancer Chemotherapy

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210514000615 ◽

2021 ◽

Vol 21 ◽

Author(s):

Aafrin Waziri ◽

Charu Bharti ◽

Mohammed Aslam ◽

Parween Jamil ◽

Aamir Mirza ◽

...

Keyword(s):

Side Effects ◽

Clinical Management ◽

Clinical Evidence ◽

Unmet Need ◽

Chemotherapeutic Agents ◽

Antitumor Effects ◽

Anti Cancer ◽

Different Types ◽

Growth Promoting ◽

High Degree

Background: The processes of chemo- and radiation therapy-based clinical management of different types of cancers are associated with toxicity and side effects of chemotherapeutic agents. So, there is always an unmet need to explore agents to reduce such risk factors. Among these, natural products have generated much attention because of their potent antioxidant and antitumor effects. In the past, some breakthrough outcomes established that various bacteria in the human intestinal gut are bearing growth-promoting attributes and suppressing the conversion of pro-carcinogens into carcinogens. Hence, probiotics integrated approaches are nowadays being explored as rationalized therapeutics in the clinical management of cancer. Methods: Here, published literature was explored to review chemoprotective roles of probiotics against toxic and side effects of chemotherapeutics. Results: Apart from excellent anti-cancer abilities, probiotics are bearing and alleviate toxicity and side effects of chemotherapeutics, with a high degree of safety and efficiency. Conclusion: Preclinical and clinical evidence suggested that due to the chemoprotective roles of probiotics against side effects and toxicity of chemotherapeutics, their integration in chemotherapy would be a judicious approach.

Download Full-text