bims-rehoca 2021-09-12 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021–09–12
twenty-two papers selected by
Vittoria Raimondi, Veneto Institute of Oncology

Reactive oxygen species and DNA damage response in cancer.
Application of glutathione depletion in cancer therapy: Enhanced ROS-based therapy, ferroptosis, and chemotherapy.
Ivermectin has New Application in Inhibiting Colorectal Cancer Cell Growth.
Crizotinib-induced anti-cancer activity in human cervical carcinoma cells via ROS-dependent mitochondrial depolarization and induction of apoptotic pathway.
Cross-Talk between Oxidative Stress and m6A RNA Methylation in Cancer.
Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells.
Rhopaloic acid A induces apoptosis, autophagy and MAPK activation through ROS-mediated signaling in bladder cancer.
Inhibition of Thioredoxin Reductase by Santamarine Conferring Anticancer Effect in HeLa Cells.
A-24, a steroidal saponin from Allium chinense, induced apoptosis, autophagy and migration inhibition in p53 wild-type and p53-deficient gastric cancer cells.
Reactive oxygen species: Role in carcinogenesis, cancer cell signaling and tumor progression.
Concurrent Reactive Oxygen Species Generation and Aneuploidy Induction Contribute to Thymoquinone Anticancer Activity.
The potentials of carbon monoxide-releasing molecules in cancer treatment: An outlook from ROS biology and medicine.
In-cell generation of anticancer phenanthridine through bioorthogonal cyclization: a paradigm in antitumor prodrug development.
Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy.
Doxorubicin-Induced Autophagolysosome Formation Is Partly Prevented by Mitochondrial ROS Elimination in DOX-Resistant Breast Cancer Cells.
The Role of the BH4 Cofactor in Nitric Oxide Synthase Activity and Cancer Progression: Two Sides of the Same Coin.
Silver Nanoparticles Modulate the Epithelial-to-Mesenchymal Transition in Estrogen-Dependent Breast Cancer Cells In Vitro.
Antioxidant/pro-oxidant and antiproliferative activities of phenolic-rich foods and extracts: A cell-based point of view.
Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux.
Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.
Targeting Mitochondrial Oxidative Phosphorylation in Glioblastoma Therapy.
Expression of Autophagy and Mitophagy Markers in Breast Cancer Tissues.

Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00049-6. [Epub ahead of print]364 139-161

Reactive oxygen species and DNA damage response in cancer.

Xavier Renaudin.

  Compared with normal cells, cancer cells often have an increase in reactive oxygen species (ROS) level. This high level of ROS allows the activation of different pathways essential for cellular transformation and tumorigenesis development. Increase of ROS can be due to increase of production or decrease of detoxification, both situations being well described in various cancers. Oxidative stress is involved at every step of cancer development from the initiation to the metastasis. How ROS arise is still a matter of debates and may vary with tissues, cell types or other conditions and may happen following a large diversity of mechanisms. Both oncogenic and tumor suppressor mutations can lead to an increase of ROS. In this chapter, I review how ROS are produced and detoxified and how ROS can damage DNA leading to the genomic instability featured in cancers.

Keywords:  Cancer; DNA damage; DNA repair; Genomic instability; Mutational signatures; Reactive oxygen species

DOI:  https://doi.org/10.1016/bs.ircmb.2021.04.001
Biomaterials. 2021 Aug 30. pii: S0142-9612(21)00466-X. [Epub ahead of print]277 121110

Application of glutathione depletion in cancer therapy: Enhanced ROS-based therapy, ferroptosis, and chemotherapy.

Boyi Niu, Kaixin Liao, Yixian Zhou, Ting Wen, Guilan Quan, Xin Pan, Chuanbin Wu.

  Glutathione (GSH) is an important member of cellular antioxidative system. In cancer cells, a high level of GSH is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. Plenty of studies have shown that loss of intracellular GSH makes cancer cells more susceptible to oxidative stress and chemotherapeutic agents. GSH depletion has been proved to improve the therapeutic efficacy of ROS-based therapy (photodynamic therapy, sonodynamic therapy, and chemodynamic therapy), ferroptosis, and chemotherapy. In this review, various strategies for GSH depletion used in cancer therapy are comprehensively summarized and discussed. First, the functions of GSH in cancer cells are analyzed to elucidate the necessity of GSH depletion in cancer therapy. Then, the synthesis and metabolism of GSH are briefly introduced to bring up some crucial targets for GSH modulation. Finally, different approaches to GSH depletion in the literature are classified and discussed in detail according to their mechanisms. Particularly, functional materials with GSH-consuming ability based on nanotechnology are elaborated due to their unique advantages and potentials. This review presents the ingenious application of GSH-depleting strategy in cancer therapy for improving the outcomes of various therapeutic regimens, which may provide useful guidance for designing intelligent drug delivery system.

Keywords:  Cancer therapy; Drug resistance; Ferroptosis; Glutathione depletion; Nanomaterials; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.biomaterials.2021.121110
Front Pharmacol. 2021 ;12 717529

Ivermectin has New Application in Inhibiting Colorectal Cancer Cell Growth.

Shican Zhou, Hang Wu, Wenjuan Ning, Xiao Wu, Xiaoxiao Xu, Yuanqiao Ma, Xingwang Li, Junhong Hu, Chenyu Wang, Junpeng Wang.

  Colorectal cancer (CRC) is the third most common cancer worldwide and still lacks effective therapy. Ivermectin, an antiparasitic drug, has been shown to possess anti-inflammation, anti-virus, and antitumor properties. However, whether ivermectin affects CRC is still unclear. The objective of this study was to evaluate the influence of ivermectin on CRC using CRC cell lines SW480 and SW1116. We used CCK-8 assay to determine the cell viability, used an optical microscope to measure cell morphology, used Annexin V-FITC/7-AAD kit to determine cell apoptosis, used Caspase 3/7 Activity Apoptosis Assay Kit to evaluate Caspase 3/7 activity, used Western blot to determine apoptosis-associated protein expression, and used flow cytometry and fluorescence microscope to determine the reactive oxygen species (ROS) levels and cell cycle. The results demonstrated that ivermectin dose-dependently inhibited colorectal cancer SW480 and SW1116 cell growth, followed by promoting cell apoptosis and increasing Caspase-3/7 activity. Besides, ivermectin upregulated the expression of proapoptotic proteins Bax and cleaved PARP and downregulated antiapoptotic protein Bcl-2. Mechanism analysis showed that ivermectin promoted both total and mitochondrial ROS production in a dose-dependent manner, which could be eliminated by administering N-acetyl-l-cysteine (NAC) in CRC cells. Following NAC treatment, the inhibition of cell growth induced by ivermectin was reversed. Finally, ivermectin at low doses (2.5 and 5 µM) induced CRC cell arrest. Overall, ivermectin suppressed cell proliferation by promoting ROS-mediated mitochondrial apoptosis pathway and inducing S phase arrest in CRC cells, suggesting that ivermectin might be a new potential anticancer drug therapy for human colorectal cancer and other cancers.

Keywords:  apoptosis; cell cycle; colorectal cancer; ivermectin; oxidative stress

DOI:  https://doi.org/10.3389/fphar.2021.717529
J Obstet Gynaecol Res. 2021 Sep 05.

Crizotinib-induced anti-cancer activity in human cervical carcinoma cells via ROS-dependent mitochondrial depolarization and induction of apoptotic pathway.

Diksha A Varma, Manisha Tiwari.

   INTRODUCTION: Cervical cancer is one of the leading causes of mortality among women population worldwide. In spite of recurrent screening, vaccination, and chemotherapeutic interventions, combating cervical cancer still remains a challenge. Crizotinib is a small molecule inhibitor that targets mesenchymal epithelial transition factor (c-MET) and has been successfully studied for its anti-cancer effects in non-small cell lung cancer, pancreatic, gastric, renal, prostate, and breast carcinomas. Although c-MET is a well-known prognostic, diagnostic, and therapeutic target in cervical cancer, anti-cancer properties of its inhibitor crizotinib against cervical carcinoma, has not been explored yet.
METHODS: In the present study, the anti-cancer effects of crizotinib on cervical cancer cells were evaluated using various in vitro cell-based assays, such as labelling drug-treated cells with MTT, H2 DCFDA, Annexin V5-fluorescein isothiocyanate (FITC) antibody, JC-1, PI, and analysis using fluorescence-activated cell sorting (FACS).
RESULTS: The molecule was found to effectively inhibit proliferation of cervical cancer cells HeLa and SiHa with an IC50 of 0.641 ± 0.0724 and 0.871 ± 0.104 μM, respectively, and induce apoptosis in a dose-dependent manner. Further investigations showed that crizotinib-induced production of reactive oxygen species (ROS) with increasing concentrations further resulted in mitochondrial membrane depolarization. However, the drug had no effect on cell cycle progression of HeLa and SiHa cells.
CONCLUSION: Thus, the study elucidates the cytotoxic effects of crizotinib in cervical cancer cells by activation of ROS-dependent apoptotic pathway via mitochondrial depolarization. These findings will further aid the evaluation of other molecular mechanisms of crizotinib and would pave the way for its implication as a chemotherapeutic option in cervical cancer.

Keywords:  ROS; apoptosis; cervical cancer; crizotinib

DOI:  https://doi.org/10.1111/jog.15003
Oxid Med Cell Longev. 2021 ;2021 6545728

Cross-Talk between Oxidative Stress and m6A RNA Methylation in Cancer.

Baishuang Yang, Qiong Chen.

Oxidative stress is a state of imbalance between oxidation and antioxidation. Excessive ROS levels are an important factor in tumor development. Damage stimulation and excessive activation of oncogenes cause elevated ROS production in cancer, accompanied by an increase in the antioxidant capacity to retain redox homeostasis in tumor cells at an increased level. Although moderate concentrations of ROS produced in cancer cells contribute to maintaining cell survival and cancer progression, massive ROS accumulation can exert toxicity, leading to cancer cell death. RNA modification is a posttranscriptional control mechanism that regulates gene expression and RNA metabolism, and m6A RNA methylation is the most common type of RNA modification in eukaryotes. m6A modifications can modulate cellular ROS levels through different mechanisms. It is worth noting that ROS signaling also plays a regulatory role in m6A modifications. In this review, we concluded the effects of m6A modification and oxidative stress on tumor biological functions. In particular, we discuss the interplay between oxidative stress and m6A modifications.

DOI: https://doi.org/10.1155/2021/6545728
Cancers (Basel). 2021 Aug 24. pii: 4266. [Epub ahead of print]13(17):

Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells.

Fang-Ping Kung, Yun-Ping Lim, Wen-Ying Chao, Yi-Sheng Zhang, Hui-I Yu, Tsai-Sung Tai, Chieh-Hsiang Lu, Shu-Hsin Chen, Yi-Zhen Li, Pei-Wen Zhao, Yu-Pei Yen, Ying-Ray Lee.

  Thyroid cancer (TC) is the most common endocrine malignancy, and its global incidence has steadily increased over the past 15 years. TC is broadly divided into well-differentiated, poorly differentiated, and undifferentiated types, depending on the histological and clinical parameters. Thus far, there are no effective treatments for undifferentiated thyroid cancers or advanced and recurrent cancer. Therefore, the development of an effective therapeutic is urgently needed for such patients. Piperlongumine (PL) is a naturally occurring small molecule derived from long pepper; it is selectively toxic to cancer cells by generating reactive oxygen species (ROS). In this study, we demonstrate the potential anticancer activity of PL in four TC cell lines. For this purpose, we cultured TC cell lines and analyzed the following parameters: Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction. PL modulated the cell cycle, induced apoptosis, and suppressed tumorigenesis in TC cell lines in a dose- and time-dependent manner through ROS induction. Meanwhile, an intrinsic caspase-dependent apoptosis pathway was observed in the TC cells under PL treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC. This is the first study to show the sensitivity of TC cell lines to PL.

Keywords:  anaplastic thyroid cancer; effective treatment; novel therapeutic strategy; recurrent thyroid cancer; safe anticancer treatment

DOI:  https://doi.org/10.3390/cancers13174266
Phytomedicine. 2021 Aug 17. pii: S0944-7113(21)00263-4. [Epub ahead of print]92 153720

Rhopaloic acid A induces apoptosis, autophagy and MAPK activation through ROS-mediated signaling in bladder cancer.

Shih-Ya Hung, Wu-Fu Chen, Yi-Chen Lee, Jui-Hsin Su, Yung-Shun Juan, In-Pin Lin, Ya-Hui Zhang, Ming-Kai Chang, Mei-Ying Lin, Chung-Yi Chen, Chien-Hsing Lee.

   BACKGROUND: Bladder cancer (BC) is a very common type of malignant cancer in men and new therapeutic strategies are urgently needed to reduce mortality. Several studies have demonstrated that Rhopaloic acid A (RA), a compound isolated from marine sponges, fights cancer but its potential anti-tumor effect on BC is still unknown.
PURPOSE: The present study was aimed to explore the potential anti-tumor effects of RA against human BC cells and the underlying molecular mechanism.
METHODS: Cell cytotoxicity was determined using the MTT and colony formation assays. Cell cycle distribution, apoptosis induction and generation of mitochondrial reactive oxygen species (ROS) were analyzed by flow cytometry. Mitochondrial membrane potential, acridine orange staining and intracellular ROS levels were observed using fluorescence microscopy. Levels of various signaling proteins were assessed using Western blotting. Furthermore, a zebrafish BC xenotransplantation model was used to confirm the anti-tumor effect of RA in vivo.
RESULTS: Treatment with RA significantly suppressed the proliferation of BC cells that resulted from G2/M cycle arrest. Additionally, RA induced mitochondrial-mediated apoptosis and autophagy in BC cells. The death of BC cells induced by RA was rescued by treatment with inhibitors of apoptosis (Z-VAD-FMA) or autophagy (3-MA). RA activated the MAPK pathway and increased the production of cellular and mitochondrial ROS. Treatment with the ROS scavenger N-acetyl cysteine, effectively reversed the induction of apoptosis, autophagy, JNK activation and DNA damage elicited by RA. Finally, RA significantly inhibited tumor growth in a zebrafish BC xenotransplantation model.
CONCLUSION: Taken together, our findings indicate that RA induces apoptosis and autophagy and activates the MAPK pathway through ROS-mediated signaling in human BC cells. This RA-induced pathway offers insights into the molecular mechanism of its antitumor effect and shows that RA is a promising candidate for the treatment of BC.

Keywords:  Autophagy; Bladder cancer; MAPK; ROS; Rhopaloic acid A; Zebrafish

DOI:  https://doi.org/10.1016/j.phymed.2021.153720
Front Mol Biosci. 2021 ;8 710676

Inhibition of Thioredoxin Reductase by Santamarine Conferring Anticancer Effect in HeLa Cells.

Junmin Zhang, Qianhe Xu, Hong-Ying Yang, Minghao Yang, Jianguo Fang, Kun Gao.

  Natural products frequently have unique physiological activities and new action mechanisms due to their structural diversity and novelty, and are an important source for innovative drugs and lead compounds. We present herein that natural product santamarine targeted thioredoxin reductase (TrxR) to weaken its antioxidative function in cells, accompanied by accumulation of high levels of reactive oxygen species (ROS), and finally induced a new mechanism of tumor cell oxidative stress-mediated apoptosis. TrxR knockdown or overexpression cell lines were employed to further evaluate the cytotoxicity of santamarine regulated by TrxR, demonstrated that TrxR played a key role in the physiological effect of santamarine on cells. Santamarine targeting TrxR reveals its previously unrecognized mechanism of antitumor and provides a basis for the further development of santamarine as a potential cancer therapeutic agent.

Keywords:  apoptosis; natural product; oxidative stress; reactive oxygen species; santamarine; thioredoxin reductase

DOI:  https://doi.org/10.3389/fmolb.2021.710676
Chem Biol Interact. 2021 Sep 07. pii: S0009-2797(21)00286-6. [Epub ahead of print] 109648

A-24, a steroidal saponin from Allium chinense, induced apoptosis, autophagy and migration inhibition in p53 wild-type and p53-deficient gastric cancer cells.

Jingwen Xu, Yihai Wang, Yi Wang, Zhe Wang, Xiangjiu He.

  Allium chinense is a vegetable with nutrition and unique flavor, and it is used as traditional Chinese medicine. We previously reported that the active compound A-24 induces apoptosis and autophagy in p53 wild-type gastric cancer cells through the PI3K/Akt/mTOR pathway. Our present work indicates that A-24 also has a significant proliferation inhibition effect on p53-deficient KATO-III cells, and the p53 status did not affect A-24 induced migration inhibition, but negatively controlled the occurrence of autophagy. We also found that the accumulation of reactive oxygen species (ROS) mediated A-24 induced apoptosis is p53-independent. Besides, p-Akt was not downregulated by A-24 in p53-deficient gastric cancer cells. Taken together, our results indicate that A-24 induced apoptosis and autophagy via the ROS-PI3K/Akt/mTOR pathway in p53 wild-type gastric cancer cells and through the ROS-mTOR pathway in p53-deficient gastric cancer cells. Our study recommended A-24 as a promising future phytotherapeutic candidate for gastric cancer treatment.

Keywords:  Allium chinense; Autophagy; ROS; Saponin; p53

DOI:  https://doi.org/10.1016/j.cbi.2021.109648
Life Sci. 2021 Sep 07. pii: S0024-3205(21)00929-2. [Epub ahead of print] 119942

Reactive oxygen species: Role in carcinogenesis, cancer cell signaling and tumor progression.

Fabiola Lilí Sarmiento-Salinas, Andrea Perez-Gonzalez, Adilene Acosta-Casique, Adrian Ix-Ballote, Alfonso Diaz, Samuel Treviño, Nora Hilda Rosas-Murrieta, Lourdes Millán-Perez-Peña, Paola Maycotte.

  Cancer is one of the major causes of death in the world and its global burden is expected to continue increasing. In several types of cancers, reactive oxygen species (ROS) have been extensively linked to carcinogenesis and cancer progression. However, studies have reported conflicting evidence regarding the role of ROS in cancer, mostly dependent on the cancer type or the step of the tumorigenic process. We review recent studies describing diverse aspects of the interplay of ROS with cancer in the different stages of cancer progression, with a special focus on their role in carcinogenesis, their importance for cancer cell signaling and their relationship to the most prevalent cancer risk factors.

Keywords:  Carcinogenesis; Neoplasm metastasis; Neoplasms; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.lfs.2021.119942
Molecules. 2021 Aug 25. pii: 5136. [Epub ahead of print]26(17):

Concurrent Reactive Oxygen Species Generation and Aneuploidy Induction Contribute to Thymoquinone Anticancer Activity.

Mohammed Al-Hayali, Aimie Garces, Michael Stocks, Hilary Collins, Tracey D Bradshaw.

  Thymoquinone (TQ) is the main biologically active constituent of Nigella sativa. Many studies have confirmed its anticancer actions. Herein, we investigated the different anticancer activities of, and considered resistance mechanisms to, TQ. MTT and clonogenic data showed TQ's ability to suppress breast MDA-MB-468 and T-47D proliferation at lower concentrations compared to other cancer and non-transformed cell lines tested (GI50 values ≤ 1.5 µM). Flow-cytometric analyses revealed that TQ consistently induced MDA-MB-468 and T-47D cell-cycle perturbation, specifically inducing pre-G1 populations. In comparison, less sensitive breast MCF-7 and colon HCT-116 cells exhibited only transient increases in pre-G1 events. Annexin V/PI staining confirmed apoptosis induction in MDA-MB-468 and HCT-116 cells, which was continuous in the former and transient in the latter. Experiments revealed the role of reactive oxygen species (ROS) generation and aneuploidy induction in MDA-MB-468 cells within the first 24 h of treatment. The ROS-scavenger NAD(P)H dehydrogenase (quinone 1) (NQO1; DT-diaphorase) and glutathione (GSH) were implicated in resistance to TQ. Indeed, western blot analyses showed that NQO1 is expressed in all cell lines in this study, except those most sensitive to TQ-MDA-MB-468 and T-47D. Moreover, TQ treatment increased NQO1 expression in HCT-116 in a concentration-dependent fashion. Measurement of GSH activity in MDA-MB-468 and HCT-116 cells found that GSH is similarly active in both cell lines. Furthermore, GSH depletion rendered these cells more sensitive to TQ's antiproliferative actions. Therefore, to bypass putative inactivation of the TQ semiquinone metabolite, the benzylamine analogue was designed and synthesised following modification of TQ's carbon-3 atom. However, the structural modification negatively impacted potency against MDA-MB-468 cells. In conclusion, we disclose the following: (i) The anticancer activity of TQ may be a consequence of ROS generation and aneuploidy; (ii) Early GSH depletion could substantially enhance TQ's anticancer activity; (iii) Benzylamine substitution at TQ's carbon-3 failed to enhance anticancer activity.

Keywords:  GSH depletion; ROS generation; aneuploidy; apoptosis; thymoquinone

DOI:  https://doi.org/10.3390/molecules26175136
Redox Biol. 2021 Sep 06. pii: S2213-2317(21)00283-4. [Epub ahead of print]46 102124

The potentials of carbon monoxide-releasing molecules in cancer treatment: An outlook from ROS biology and medicine.

Thi Thuy Tien Vo, Quang Canh Vo, Vo Phuoc Tuan, Yinshen Wee, Hsin-Chung Cheng, I-Ta Lee.

  Carbon monoxide (CO) is now well recognized a pivotal endogenous signaling molecule in mammalian lives. The proof-of-concept employing chemical carriers of exogenous CO as prodrugs for CO release, also known as CO-releasing molecules (CO-RMs), has been appreciated. The major advantage of CO-RMs is that they are able to deliver CO to the target sites in a controlled manner. There is an increasing body of experimental studies suggesting the therapeutic potentials of CO and CO-RMs in different cancer models. This review firstly presents a short but crucial view concerning the characteristics of CO and CO-RMs. Then, the anticancer activities of CO-RMs that target many cancer hallmarks, mainly proliferation, apoptosis, angiogenesis, and invasion and metastasis, are discussed. However, their anticancer activities are varying and cell-type specific. The aerobic metabolism of molecular oxygen inevitably generates various oxygen-containing reactive metabolites termed reactive oxygen species (ROS) which play important roles in both physiology and pathophysiology. Although ROS act as a double-edged sword in cancer, both sides of which may potentially have been exploited for therapeutic benefits. The main focus of the present review is thus to identify the possible signaling network by which CO-RMs can exert their anticancer actions, where ROS play the central role. Another important issue concerning the potential effect of CO-RMs on the aerobic glycolysis (the Warburg effect) which is a feature of cancer metabolic reprogramming is given before the conclusion with future prospects on the challenges of developing CO-RMs into clinically pharmaceutical candidates in cancer therapy.

Keywords:  Apoptosis; Carbon monoxide; Carbon monoxide-releasing molecules; Pro-tumorigenic pathways; Reactive oxygen species; Warburg effect

DOI:  https://doi.org/10.1016/j.redox.2021.102124
Angew Chem Int Ed Engl. 2021 Sep 06.

In-cell generation of anticancer phenanthridine through bioorthogonal cyclization: a paradigm in antitumor prodrug development.

Hichem Maslah, Charles Skarbek, Catherine Gourson, Marie-Aude Plamont, Stéphanie Pethe, Ludovic Jullien, Thomas Le Saux, Raphael T Labruere.

  Pharmacological inactivation of antitumor drugs toward healthy cells is a critical factor in prodrug development. Typically, pharmaceutical chemists graft temporary moieties to existing antitumor drugs to reduce their pharmacological activity as much as possible. Here, we report a platform where the structure of the prodrug excludes the preexisting antitumor drug motif and is based on an inactive synthetic precursor able to generate the cytotoxic agent by bioorthogonal cyclization within a tumor environment. Using phenanthridines as cytotoxic model compounds, we designed ring-opened biaryl precursors that generated the phenanthridines through bioorthogonal irreversible imination. This reaction was triggered by reactive oxygen species, commonly overproduced in cancer cells, able to convert a vinyl boronate ester function into a ketone that subsequently reacted with a pendant aniline. An inactive precursor was shown to engender a cytotoxic phenanthridine against KB cancer cells. Moreover, the kinetic of cyclization of this prodrug was extremely rapid (˂ 10 ms) inside living cells of KB cancer spheroids so as to circumvent drug action.

Keywords:  Antitumor agents; Phenanthridine; bioorthogonal chemistry; prodrug; reactive oxygen species

DOI:  https://doi.org/10.1002/anie.202110041
Front Mol Biosci. 2021 ;8 706650

Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy.

Caterina Bartolacci, Cristina Andreani, Yasmin El-Gammal, Pier Paolo Scaglioni.

  HRAS, NRAS and KRAS, collectively referred to as oncogenic RAS, are the most frequently mutated driver proto-oncogenes in cancer. Oncogenic RAS aberrantly rewires metabolic pathways promoting the generation of intracellular reactive oxygen species (ROS). In particular, lipids have gained increasing attention serving critical biological roles as building blocks for cellular membranes, moieties for post-translational protein modifications, signaling molecules and substrates for ß-oxidation. However, thus far, the understanding of lipid metabolism in cancer has been hampered by the lack of sensitive analytical platforms able to identify and quantify such complex molecules and to assess their metabolic flux in vitro and, even more so, in primary tumors. Similarly, the role of ROS in RAS-driven cancer cells has remained elusive. On the one hand, ROS are beneficial to the development and progression of precancerous lesions, by upregulating survival and growth factor signaling, on the other, they promote accumulation of oxidative by-products that decrease the threshold of cancer cells to undergo ferroptosis. Here, we overview the recent advances in the study of the relation between RAS and lipid metabolism, in the context of different cancer types. In particular, we will focus our attention on how lipids and oxidative stress can either promote or sensitize to ferroptosis RAS driven cancers. Finally, we will explore whether this fine balance could be modulated for therapeutic gain.

Keywords:  RAS oncogenes; ferroptosis; lipid metabolism; oxidative stress; tumorigenesis

DOI:  https://doi.org/10.3389/fmolb.2021.706650
Int J Mol Sci. 2021 Aug 27. pii: 9283. [Epub ahead of print]22(17):

Doxorubicin-Induced Autophagolysosome Formation Is Partly Prevented by Mitochondrial ROS Elimination in DOX-Resistant Breast Cancer Cells.

Seyedeh Tayebeh Ahmadpour, Valérie Desquiret-Dumas, Ulku Yikilmaz, Julie Dartier, Isabelle Domingo, Celine Wetterwald, Charlotte Orre, Naïg Gueguen, Lucie Brisson, Karine Mahéo, Jean-François Dumas.

  Since its discovery, mitophagy has been viewed as a protective mechanism used by cancer cells to prevent the induction of mitochondrial apoptosis. Most cancer treatments directly or indirectly cause mitochondrial dysfunction in order to trigger signals for cell death. Elimination of these dysfunctional mitochondria by mitophagy could thus prevent the initiation of the apoptotic cascade. In breast cancer patients, resistance to doxorubicin (DOX), one of the most widely used cancer drugs, is an important cause of poor clinical outcomes. However, the role played by mitophagy in the context of DOX resistance in breast cancer cells is not well understood. We therefore tried to determine whether an increase in mitophagic flux was associated with the resistance of breast cancer cells to DOX. Our first objective was to explore whether DOX-resistant breast cancer cells were characterized by conditions that favor mitophagy induction. We next tried to determine whether mitophagic flux was increased in DOX-resistant cells in response to DOX treatment. For this purpose, the parental (MCF-7) and DOX-resistant (MCF-7dox) breast cancer cell lines were used. Our results show that mitochondrial reactive oxygen species (ROS) production and hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression are higher in MCF-7dox in a basal condition compared to MCF-7, suggesting DOX-resistant breast cancer cells are prone to stimuli to induce a mitophagy-related event. Our results also showed that, in response to DOX, autophagolysosome formation is induced in DOX-resistant breast cancer cells. This mitophagic step following DOX treatment seems to be partly due to mitochondrial ROS production as autophagolysosome formation is moderately decreased by the mitochondrial antioxidant mitoTEMPO.

Keywords:  breast cancer; doxorubicin; mitochondria; mitophagy; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms22179283
Int J Mol Sci. 2021 Sep 02. pii: 9546. [Epub ahead of print]22(17):

The Role of the BH4 Cofactor in Nitric Oxide Synthase Activity and Cancer Progression: Two Sides of the Same Coin.

Diego Assis Gonçalves, Miriam Galvonas Jasiulionis, Fabiana Henriques Machado de Melo.

  Cancer development is associated with abnormal proliferation, genetic instability, cell death resistance, metabolic reprogramming, immunity evasion, and metastasis. These alterations are triggered by genetic and epigenetic alterations in genes that control cell homeostasis. Increased reactive oxygen and nitrogen species (ROS, RNS) induced by different enzymes and reactions with distinct molecules contribute to malignant transformation and tumor progression by modifying DNA, proteins, and lipids, altering their activities. Nitric oxide synthase plays a central role in oncogenic signaling modulation and redox landscape. Overexpression of the three NOS isoforms has been found in innumerous types of cancer contributing to tumor growth and development. Although the main function of NOS is the production of nitric oxide (NO), it can be a source of ROS in some pathological conditions. Decreased tetrahydrobiopterin (BH4) cofactor availability is involved in NOS dysfunction, leading to ROS production and reduced levels of NO. The regulation of NOSs by BH4 in cancer is controversial since BH4 has been reported as a pro-tumoral or an antitumoral molecule. Therefore, in this review, the role of BH4 in the control of NOS activity and its involvement in the capabilities acquired along tumor progression of different cancers was described.

Keywords:  cancer; nitric oxide synthase; sepiapterin; tetrahydrobiopterin

DOI:  https://doi.org/10.3390/ijms22179546
Int J Mol Sci. 2021 Aug 25. pii: 9203. [Epub ahead of print]22(17):

Silver Nanoparticles Modulate the Epithelial-to-Mesenchymal Transition in Estrogen-Dependent Breast Cancer Cells In Vitro.

Michał Rakowski, Szymon Porębski, Agnieszka Grzelak.

  Silver nanoparticles (AgNPs) are frequently detected in many convenience goods, such as cosmetics, that are applied directly to the skin. AgNPs accumulated in cells can modulate a wide range of molecular pathways, causing direct changes in cells. The aim of this study is to assess the capability of AgNPs to modulate the metastasis of breast cancer cells through the induction of epithelial-to-mesenchymal transition (EMT). The effect of the AgNPs on MCF-7 cells was investigated via the sulforhodamine B method, the wound healing test, generation of reactive oxygen species (ROS), the standard cytofluorimetric method of measuring the cell cycle, and the expression of EMT marker proteins and the MTA3 protein via Western blot. To fulfill the results, calcium flux and HDAC activity were measured. Additionally, mitochondrial membrane potential was measured to assess the direct impact of AgNPs on mitochondria. The results indicated that the MCF-7 cells are resistant to the cytotoxic effect of AgNPs and have higher mobility than the control cells. Treatment with AgNPs induced a generation of ROS; however, it did not affect the cell cycle but modulated the expression of EMT marker proteins and the MTA3 protein. Mitochondrial membrane potential and calcium flux were not altered; however, the AgNPs did modulate the total HDAC activity. The presented data support our hypothesis that AgNPs modulate the metastasis of MCF-7 cells through the EMT pathway. These results suggest that AgNPs, by inducing reactive oxygen species generation, alter the metabolism of breast cancer cells and trigger several pathways related to metastasis.

Keywords:  MCF-7; breast cancer; epithelial–mesenchymal transition; estrogen; metastasis; silver nanoparticles

DOI:  https://doi.org/10.3390/ijms22179203
Adv Food Nutr Res. 2021 ;pii: S1043-4526(21)00015-2. [Epub ahead of print]98 253-280

Antioxidant/pro-oxidant and antiproliferative activities of phenolic-rich foods and extracts: A cell-based point of view.

Mariana Araújo Vieira do Carmo, Daniel Granato, Luciana Azevedo.

  Phenolic compounds have demonstrated several in vitro beneficial properties by acting as antioxidant and pro-oxidant agents. This chapter approaches the relationship among oxidative stress, cancer, phenolic compounds and antiproliferative activity. Moreover, it discusses in vitro techniques and their biological applications, regarding cell viability and intracellular measure of reactive oxygen assays. The in vitro methods are important tools for screening and understanding the pathways involved on antiproliferative and antioxidant/pro-oxidant effects of phenolic compounds. These findings open avenues for the development of innovative food, chemical structures, technological applications and future perspectives in this research field.

Keywords:  Cancer; Cell culture; Cell viability; In vitro methods; Oxidative stress; Phenolic compounds; Reactive oxygen species

DOI:  https://doi.org/10.1016/bs.afnr.2021.02.010
Biol Res. 2021 Sep 06. 54(1): 27

Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux.

Dong-Lin Yang, Ya-Jun Zhang, Liu-Jun He, Chun-Sheng Hu, Li-Xia Gao, Jiu-Hong Huang, Yan Tang, Jie Luo, Dian-Yong Tang, Zhong-Zhu Chen.

   BACKGROUND: Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied.
RESULTS: In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin.
CONCLUSIONS: Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic.

Keywords:  Apoptosis; Autophagic flux; CaP; Cisplatin; ER stress; T-96

DOI:  https://doi.org/10.1186/s40659-021-00350-6
Blood Adv. 2021 Sep 10. pii: bloodadvances.2020003661. [Epub ahead of print]

Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.

Kaori Saito, Qi Zhang, Haeun Yang, Kotoko Yamatani, Tomohiko Ai, Vivian Ruvolo, Natalia Baran, Tianyu Cai, Helen Ma, Rodrigo Jacamo, Vinitha Mary Kuruvilla, Junichi Imoto, Sonoko Kinjo, Kazuho Ikeo, Kaori Moriya, Koya Suzuki, Takashi Miida, Yong-Mi Kim, Christopher P Vellano, Michael Andreeff, Joseph R Marszalek, Yoko Tabe, Marina Y Konopleva.

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival and continually adapt to fluctuations in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. Cellular adhesion, growth, and apoptosis assays, along with measurements of mtDNA expression and mitochondrial reactive oxygen species generation, indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, OxPhos inhibition induced (1) transfer of mesenchymal stem cell (MSC)-derived mitochondria to AML cells via tunneling nanotubes under direct-contact coculture conditions, and (2) mitochondrial fission with an increase in functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, and we observed mitochondrial transport to the leading edge of protrusions of migrating AML cells toward MSCs by electron microscopy analysis. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased OxPhos inhibition-triggered mitochondrial transfer from MSCs to AML cells. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.

DOI: https://doi.org/10.1182/bloodadvances.2020003661
Neuromolecular Med. 2021 Sep 06.

Targeting Mitochondrial Oxidative Phosphorylation in Glioblastoma Therapy.

Zhihao Wu, Winson S Ho, Rongze Lu.

  As a multi-functional cellular organelle, mitochondrial metabolic reprogramming is well recognized as a hallmark of cancer. The center of mitochondrial metabolism is oxidative phosphorylation (OXPHOS), in which cells use enzymes to oxidize nutrients, thereby converting the chemical energy to the biological energy currency ATPs. OXPHOS also creates the mitochondrial membrane potential and serve as the driving force of other mitochondrial metabolic pathways and experiences significant reshape in the different stages of tumor progression. In this minireview, we reviewed the major mitochondrial pathways that are connected to OXPHOS and are affected in cancer cells. In addition, we summarized the function of novel bio-active molecules targeting mitochondrial metabolic processes such as OXPHOS, mitochondrial membrane potential and mitochondrial dynamics. These molecules exhibit intriguing preclinical and clinical results and have been proven to be promising antitumor candidates in recent studies.

Keywords:  Glioblastoma; Mitochondrial dysfunction; OXPHOS inhibitors

DOI:  https://doi.org/10.1007/s12017-021-08678-8
Front Oncol. 2021 ;11 612009

Expression of Autophagy and Mitophagy Markers in Breast Cancer Tissues.

Mohd Fazirul Mustafa, Suhainizam Muhamad Saliluddin, Sharida Fakurazi, Nur Maya Sabrina Tizen Laim, Suria Hayati Md Pauzi, Nik Hasimah Nik Yahya, Navarasi S Raja Gopal, Maizaton Atmadini Abdullah, Sandra Maniam.

  Mitochondria play important roles in regulating cell bioenergetics status and reactive oxygen species (ROS) generation. ROS-induced mitochondrial damage is among the main intracellular signal inducers of autophagy. Autophagy is a cellular catabolic process that regulates protein and organelle turnover, while a selective form of autophagy, mitophagy, specifically targets dysfunctional mitochondrial degradation. This study aims to measure the levels of autophagy, mitophagy, oxidative stress, and apoptosis in invasive breast carcinoma tissues using immunohistochemistry (IHC). Tissue microarrays of 76 patients with breast cancer were stained with six IHC markers (MnSOD, Beclin-1, LC3, BNIP3, Parkin, and cleaved caspase 3). The expression intensity was determined for each tumor tissue and the adjacent tumor-matched control tissues. Intermediate and strong staining scores of MnSOD, Beclin-1, LC-3, BNIP-3, and Parkin were significantly higher in tumor tissues compared to the adjacent matched control. The scoring intensity was further classified into tissues with negative staining and positive staining, which showed that positive scores of Beclin-1 and Parkin were significantly high in tumor tissues compared to other markers. Positive association was also noted between BNIP-3 and Beclin-1 as well as LC-3 and cleaved caspase-3 immunostaining. To our knowledge, this is one of the first studies that measure both mitophagy and autophagy in the same breast cancer tissues and the adjacent matched control. The findings from this study will be of great potential in identifying new cancer biomarkers and inspire significant interest in applying anti-autophagy therapies as a possible treatment for breast cancer.

Keywords:  autophagy; breast cancer; immunohistochemistry; mitophagy; oxidative stress

DOI:  https://doi.org/10.3389/fonc.2021.612009