Iodinated contrast agents are a class of compounds widely used in diagnostic medicine to enhance images of tissues subjected to X-ray techniques. Previous studies have shown that radiocontrast agents are capable of increasing the generation of reactive oxygen species (ROS) and inducing the activation of apoptosis in tumor cells, making these compounds an alternative for cancer treatment. However, there is a lack of studies on their antitumor action in chemotherapy-resistant tumors. Here, we evaluate the cytotoxicity of the iodinated contrast agents TIBA (triiodobenzoic acid) and iohexol in cell lines with different resistance profiles: glioblastoma (A172), parental (K562) and chemotherapy-resistant (Lucena 1) chronic myeloid leukemia. The normal renal epithelial cell line (VERO) was used to evaluate the cytotoxic effects of these compounds in non-tumoral cells. After treatment with TIBA and iohexol at different concentrations, cell viability, ROS, cell death, mitochondrial membrane potential, activity of proteins involved in the multidrug resistance phenotype, glucose influx and migration of glioblastoma cell lines and spheroids were evaluated. Both contrast agents were cytotoxic against Lucena 1 and A172 in a dose-dependent manner. In spheroids, iohexol was the most cytotoxic compound. Furthermore, we demonstrated that cell death induced by contrast agents involves ROS generation. TIBA and iohexol also cause loss of mitochondrial membrane potential in Lucena1 and VERO, inhibit Pgp and MRP1 activity in Lucena 1 and A172, modulate glucose influx and decrease cell migration of A172 cells. We conclude that TIBA and iohexol are promising drugs for adjuvant use in the treatment of chemotherapy-resistant tumors.

BACKGROUND AND OBJECTIVE:Cancer is a public health problem and is considered the leading cause of death around the globe. Despite the advances in cancer therapies, many patients suffer from adverse side effects and drug resistance. Among the cancer hallmarks, metabolic reprogramming is essential for supporting the higher energy demand of cancer cells. Due to the Warburg effect, a misconception that oxidative phosphorylation (OXPHOS) and other mitochondrial-related metabolic pathways are dispensable for tumor cells was created. Nowadays, many studies have been demonstrating the importance of mitochondria and their metabolism to cancer bioenergetics and progression. Through this review, we aim to show natural compounds that regulate mitochondrial metabolism to exert their anticancer activity. METHODS:In this literature review, studies found in PubMed, in English and published between 1925-2025 were considered. KEY CONTENT AND FINDINGS:Throughout this review, we discussed the importance of mitochondrial metabolism for carcinogenesis, updated and brought new natural products as potential therapies to target mitochondrial metabolism to counteract cancer progression. Furthermore, we discussed the future directions to overcome the limitations of the use of natural products as anticancer compounds. CONCLUSIONS:Natural compounds can act in different pathways of mitochondrial metabolism to exert their antitumoral effects, however, some limitations need to be overcome. Developing natural product-based hybrids through the conjugation of natural compounds with bioactive molecules has gained interest to surpass these limitations, representing a good strategy to enhance the anticancer treatment effectiveness of natural products.

BACKGROUND AND OBJECTIVE:Hematological malignancies (HMs) are a group of neoplasms with hematopoietic origin, currently divided into leukemias, lymphomas and multiple myeloma (MM). Although the advances in the management of HMs, the rate of drug resistance, relapse and refractory disease has been increasing, requiring new therapeutic strategies. In this review, we aim to summarize metformin's antitumoral mechanisms of action and present the latest studies of metformin action in HMs, including in resistant ones. METHODS:For this review of literature, studies published between 1996 and 2023 from PubMed and clinical trials submitted to clinicaltrials.gov were considered. KEY CONTENT AND FINDINGS:Throughout this review we demonstrated the capacity of metformin to act as an anti-HMs drug, being able to re-sensitize HMs to classical anti-HMs agents and to overcome relapse and refractory HMs, as shown in vitro and in vivo studies. Associated with the potential anti-HM effect of metformin, some clinical trials are in progress, including in the view of reducing resistance and recurrence rate of HMs, which requires further exploration. The relationship among HMs cancer stem cells (HMs CSCs), drug resistance, cancer recurrence, and the effect of metformin in inhibiting CSCs were also discussed, despite this field needing more attention. CONCLUSIONS:In summary, metformin is a promising anti-HMs drug that can enhance patients' survival and prognosis through its action in the improvement of HMs response.

Pomolic acid (3-beta,19alpha-Dihydroxy-urs-12-en-28-oic acid, PA) is a naturally occurring pentacyclic triterpenoid. Derived from the mevalonate pathway through cyclization of 2,3-oxidosqualene, it has been widely found in several plant species. In the mid-1960s, PA was identified as the genuine aglycone of triterpenoid saponins from Sanguisorba officinalis, and studies on its biological activities began in 1989. Since then, several pharmacological properties have been described for this compound, including antitumoral activity. PA induced cell death in tumors, such as lung, brain, breast, and sensitive and resistant leukemia. Additionally, PA modulates resistant proteins and events involved in metastasis. Even though PA constitutes an important candidate for new treatment against several cancers, its availability hampers the evolution of PA studies toward clinical evaluation. This review discusses the limitations of PA availability, the recent approaches to improve it, and other aspects of the antitumoral studies on PA activity.

Abstract Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors. Chemicals and target-directed therapy have been used to treat these tumors, but the development of resistance has hampered patient treatment. Thus, many researchers are seeking new compounds that are capable of reversing resistance. Plants from the Brazilian Amazon, such as Apuleia leiocarpa, represent an alternative source of new compounds with the potential to treat lung cancer. Increasing concentrations of A. leiocarpa extracts (25, 50 and 100 µg/ml) from stem, sapwood, root, and stem bark were tested against an NSCLC cell line (H460) for 48 h. The dichloromethane-stem (ALE3) and ethanolic-stem bark (ALE5) extracts inhibited cell viability and were further evaluated for apoptosis, loss of mitochondrial membrane potential (MMP), and expression of proteins belonging to the apoptotic and autophagic pathway. The results indicated that ALE3 and ALE5 induced dose-dependent apoptosis and loss of MMP, and while ALE3 induced the expression of apoptotic markers p53 and active caspase 3, ALE5 induced the expression of autophagy markers Beclin-1, ATG12 and LC3II. This study demonstrates for the first time that Apuleia leiocarpa possess significant antitumoral potential to fight lung cancer.

DNA and Cell BiologyVol. 42, No. 6 EditorialFree AccessExpanding Opportunities in Viral OncolysisJanaina FernandesJanaina FernandesAddress correspondence to: Janaina Fernandes, PhD, NUMPEX-BIO, Campus Santa Cruz da Serra, Av. Pastor Manuel Avelino de Souza 27, Duque de Caxias, Rio de Janeiro 21949-900, Brazil E-mail Address: [email protected]https://orcid.org/0000-0002-3442-6101NUMPEX-BIO, Campus Santa Cruz da Serra, Rio de Janeiro, Brazil.Search for more papers by this authorPublished Online:2 Jun 2023https://doi.org/10.1089/dna.2023.0129.editorialAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookXLinked InRedditEmail Oncolytic Viruses (OVs) preferentially infect and lyse cancer cells either naturally, or through modifications that improve its efficiency and reduce its virulence. In addition, nonreplicating viral vectors can be used to carry therapeutic genes that are able to target tumor cells inducing cell death and antitumoral immunity. Oncolysis has been grown as a response to the radio- and drug-resistance phenomena, where malignant tumors stop responding to conventional and target-directed therapies, immunotherapy, and its combinations.For this DNA and Cell Biology Special Focus on viral oncolysis, the selected authors bring us an innovative and integrated vision on the subject and provide state-of-the-art information on some of the challenges of the field, so as the discussion on the potential to expand this therapeutic approach to include new viral alternatives and new targets that have not yet been considered, as pathogenic unicellular parasites.Mendonça and colleagues bring new data regarding the use of nonreplicating adenoviral vectors used for p14ARF and interferon-b (hIFNb) gene transfer in human melanoma cell lines. In this study, p14ARF (alternative reading frame of CDKN2a, p14ARF in humans, p19Arf in mice) and interferon-b (IFNb) genes were shown to induced oncolysis accompanied by immunogenic cell death markers and upregulation of genes involved in immune regulation. These data reflect an improvement of the viral vector approach for melanoma.In a review, Zhou and colleagues discussed the potential of Zika virus (ZIKV) as OVs. ZIKV, a mosquito-borne flavivirus, was shown to preferentially target neural cells, which is particularly harmful to embryo development, leading to microcephaly and severe neurological disease. In contrast, Zika infection in adults is usually symptomless or cause only mild symptoms. ZIKV's natural tropism toward glioma cells and the promising therapeutic effects in treating glioblastoma multiforme (GBM) in preclinical models are discussed in this review. Also, the authors discuss the candidate surface receptors responsible for the ZIKV tropism toward GBM, and the combinatory therapy involving immunotherapy and checkpoint inhibitors.Siew and colleagues explored the potential of zoonotic viruses of the Reoviridae family as OVs. Despite the tropism of some viruses toward tumor cells, the use of wild-type viruses raises concerns regarding cross-species viral transmission risk and autoimmune response to the therapy. Thus, genetic modifications were introduced to reduce the pathogenicity of OV and improve its anticancer efficacy. In this review, is presented a historical perspective of the use of reovirus as an oncolytic virus. And it is also highlighted some family members of interest and their mode of action. Avian and pteropine reoviruses potential are updated. Concerns and challenges over these zoonotic reoviruses are discussed so as clinical and preclinical studies of oncolytic reoviruses.The work of Fernandes brings a discussion of the possible expansion of viral-mediated lysis to biological entities other than tumors. The review focuses on other virus-eukaryotic cell interactions that may provide important insights on the possibility to transpose viral oncolysis to Leishmaniasis and other neglected diseases. The article explores the natural interaction between viruses and Leishmania species, as well as the similarities among the outcomes of viral infections of amoeba and yeast with tumors, highlighting the importance of viral-like particles as well as the vesicular system's features and its potential to allow viral-induced lysis of intracellular parasites, or at least reduce its virulence.This series of articles contemplates the need to discuss perspectives on the application of viral oncolysis in the near future, pushing some boundaries of this exciting field of knowledge.We hope the readers enjoy these engaging discussions.Author's ContributionJ.F. wrote the article.Disclosure StatementNo competing financial interests exist.Funding InformationThis study was supported by FAPERJ—Fundação Carlos Chagas Filho de Amparo à Pesquisa do Rio de Janeiro (grant E-26/211.058/2021).ReferencesMendonça AS, Antunes F, Cerqueira OLD, Del Valle PR, Hunger A, de Oliveira PVS, Brito B, Costanzi-Strauss E, Strauss BE. Induction of immune-stimulating factors and oncolysis upon p14ARF gene transfer in melanoma cell lines. DNA and Cell Biology. 2023. Published Online: 20 December 2022. doi: 10.1089/dna.2022.0115. Link, Google ScholarSiew , ZY, Loh , A, Segeran , S, Leong , PP, Voon , K. Oncolytic reoviruses: Can these emerging zoonotic reoviruses be tamed and utilized? DNA and Cell Biology, 2023. Published Online: 4 April 2023. doi: 10.1089/dna.2022.0561. Link, Google ScholarZhou C, Chen Q, Chen Y, Qin C-F. Oncolytic zika virus: New option for glioblastoma treatment. DNA and Cell Biology, 2023. Published Online: 9 November 2022. doi: 10.1089/dna.2022.0375. Link, Google ScholarFiguresReferencesRelatedDetails Volume 42Issue 6Jun 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Janaina Fernandes.Expanding Opportunities in Viral Oncolysis.DNA and Cell Biology.Jun 2023.265-266.http://doi.org/10.1089/dna.2023.0129.editorialPublished in Volume: 42 Issue 6: June 2, 2023Online Ahead of Print:May 10, 2023Keywordsviral oncolysisgliomamelanomaviral vectorLeishmaniasisPDF download

This article is focused on the main pathways used by viruses to achieve infection and lysis of unicellular eukaryotes described as pathogenic for multicellular organisms. In light of the recent discussions on how tumor cells exhibit unicellular behavior, highly malignant cells can be considered as another unicellular pathogenic entity, but with endogenous origin. Thus, a comparative panel of viral lysis of exogenous pathogenic unicellular eukaryotes such as Acanthamoeba sp., yeast, and tumors is presented. The important intracellular parasite Leishmania sp is also presented, which, in contrast, has its virulence improved by viral infections. The possible exploitation of viral-mediated eukaryotic cell lysis to overcome infections of Leishmania sp is discussed.

Assay of drug efflux pump activity (PgP and MRP1) in chemotherapy-resistant cells, assay done by flow cytometry after treatment with iodinated contrast agents

Gap junction intercellular communication (GJIC) is considered a key mechanism in the regulation of tissue homeostasis. GJIC structures are organized in two transmembrane channels, with each channel formed by connexins (Cxs). GJIC and Cxs expression alterations are related to the process of tumorigenesis in different cell types. Pituitary neuroendocrine tumors (PitNETs) represent 15–20% of intracranial neoplasms, and usually display benign behavior. Nevertheless, some may have aggressive behavior, invading adjacent tissues, and featuring a high proliferation rate. We aimed to assess the expression and relevance of GJIC and Cxs proteins in PitNETs. We evaluated the mRNA expression levels of Cx26, 32, and 43, and the protein expression of Cx43 in a series of PitNETs. In addition, we overexpressed Cx43 in pituitary tumor cell lines. At the mRNA level, we observed variable expression of all the connexins in the tumor samples. Cx43 protein expression was absent in most of the pituitary tumor samples that were studied. Moreover, in vitro studies revealed that the overexpression of Cx43 decreases cell growth and induces apoptosis in pituitary tumor cell lines. Our results indicate that the downregulation of Cx43 protein might be involved in the tumorigenesis of most pituitary adenomas and have a potential therapeutic value for pituitary tumor therapy.

The intestinal microbiota is considered a large organ in the human body performing functions in the host that range from supporting digestion and absorption of nutrients from the diet to regulating the various processes in the host. Maintaining a diverse and stable microbiota is critical to maintaining host homeostasis and health. Studies have suggested the relationship between the microbial changes and the development of several pathologies. In this context, metformin, has shown to be a promising drug for the regulation of the microbiota, thus favoring the prevention and treatment of type 2 diabetes mellitus (T2DM), obesity, cancer, the inflammatory state of human immunodeficiency virus (HIV), heart disease, Alzheimer's disease and aging, and pathologies associated with dysbiosis. In this review, the main aspects on the importance of metformin's action on dysbiosis, and the factors that regulate the metformin uptake and activity as genetic polymorphisms and GLP-1 receptor activation were discussed.

Olfactory ensheathing cells (OECs) are a unique type of macroglia with axonal growth‐promoting properties. The migrating ability of OECs in CNS is essential for neural regeneration. However, little is known about the extracellular and intracellular factors that regulate OEC migration. In the present study, we examined the effects of glial cell line‐derived neurotrophic factor (GDNF) on OECs migration. Initially, the “scratch” migration assay, Boyden chamber assay, and explant migration assay showed that GDNF could promote OECs migration in vitro. Treatment of OECs with GDNF also induced cytoskeleton reorganization and up‐regulated expression of cytoskeleton proteins. GDNF‐induced OECs migration was demonstrated depending on GFRα‐1 and Ret receptor, and activation of JNK and Src signaling cascades. Furthermore, GDNF was found to promote implanted OECs migration in a spinal cord hemisection injury model. Together, we report, to our knowledge for the first time, that GDNF stimulate OECs migration in vitro and in vivo. © 2006 Wiley‐Liss, Inc.

Tumor lysis syndrome (TLS) is a metabolic disorder that mainly affects patients with malignant hematological neoplasms, and its development is frequently related to uric acid accumulation (hyperuricemia). Rasburicase is a recombinant urate oxidase enzyme applied to treat and avoid TLS converting urate into allantoin, a compound easily eliminated by the kidneys. However, a recent study by the authors demonstrated in vitro that an elevated allantoin generation, which has been observed in oncological patients treated with rasburicase, reduced cisplatin cytotoxicity in a non‑small cell lung cancer cell line (H460). Thus, it is necessary to determine the effects of the concomitant use of cisplatin and rasburicase for the treatment of patients with chronic myeloid leukemia (CML); due to the higher incidence of tumor lysis syndrome among patients with CML, it is necessary to search for adjuvant agents that can restore cisplatin cytotoxicity. Among adjuvant agents, metformin is of interest as it is effective, safe and has established pharmacological parameters. Thus, the present study evaluated the capacity of metformin to restore allantoin‑reduced cisplatin cytotoxicity in a CML cell line (K562) in vitro. The cells were treated with metformin (0.1, 0.25, 0.5, 0.6025, 2, 2.5 and 3 mM), cisplatin (15, 16.5, 20, 30 and 33 µM), allantoin (100 and 200 µg/ml), or their combinations for 48 h. Cell viability, cell cycle, morphological analysis and nuclear magnetic resonance experiments were performed. The results revealed that allantoin reduced cisplatin cytotoxicity in the K562 cell line. Thus, metformin synergistically increased cisplatin‑induced cell death and restored the cisplatin cytotoxicity that was reduced by allantoin.

DNA and Cell BiologyVol. 39, No. 2 Call for PapersFree AccessCall for Special Issue Papers: Viral OncolysisDeadline for Manuscript Submission: March 31, 2020Guest Editor: Janaina FernandesGuest Editor: Janaina FernandesUniversidade Federal do Rio de JaneiroSearch for more papers by this authorPublished Online:30 Jan 2020https://doi.org/10.1089/dna.2019.29013.cfp4AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Infection of a tumor cell with a replication-competent virus, can result in the destruction of the tumor, but spares the neighboring normal cells; this is a new tool to treat cancer. These viruses are modified to specifically target cancer cells. In addition, this can lead to induction of host immune response to tumor cell antigens.DNA and Cell Biology is organizing a special issue on Viral Oncolysis. We are looking for papers that will bring an innovative and integrated vision on the subject and provide state of the art information on the role of viral oncolysis in solid and hematological cancers to the scientific community.We will consider articles highlighting the full breadth of scientific findings in the form of original research papers and reviews.Areas of interest include, but are not limited to: Review of Viral OncolysisMechanisms of Resistance of tumors to Viral OncolysisTreatment of solid and circulating tumorsMarkers of clinical efficacy of treatmentNew candidate viruses for viral oncolysisCheckpoint inhibitors and viral oncolysisVeterinary applications of viral oncolysisAdjuvant therapy and viral oncolysisIn vivo studiesClinical trialsGenetic variation among viruses used in oncolysis applicationsContributions will receive prompt and thorough peer review. Please refer to our Instructions for Authors before submitting your manuscript for consideration. Authors are encouraged to vet ideas directly with Carol Shoshkes Reiss, our editor-in-chief, and Janaina Fernandes, the guest editor of the Special Focus issue via e-mail before submitting. Instructions for Authors can be found on our website at www.liebertpub.com/dnaDNA and Cell Biology delivers authoritative, peer-reviewed research on all aspects of molecular and cellular biology, with a unique focus on combining mechanistic and clinical studies to drive the field forward. The journal is under the editorial leadership of Editor-in-Chief Carol Shoshkes Reiss, PhD, Departments of Biology and Neural Science, New York University, and other leading investigators.Editorial QuestionsJanaina Fernandes, Guest Editor, E-mail:janainaf@biof.ufrj.brCarol Shoshkes Reiss, Editor-in-Chief, E-mail:carol.reiss@nyu.eduSubmit your paper for peer review online:https://mc.manuscriptcentral.com/dnaFiguresReferencesRelatedDetails Volume 39Issue 2Feb 2020 InformationCopyright 2020, Mary Ann Liebert, Inc., publishersTo cite this article:Guest Editor: Janaina Fernandes.Call for Special Issue Papers: Viral Oncolysis.DNA and Cell Biology.Feb 2020.153-153.http://doi.org/10.1089/dna.2019.29013.cfp4Published in Volume: 39 Issue 2: January 30, 2020Online Ahead of Print:January 16, 2020PDF download

Massive lysis of tumor mass in cancer patients under chemotherapy regimens generates high levels of uric acid, leading to what is known as tumor lysis syndrome (TLS). Rasburicase, a recombinant urate oxidase, converts urate to allantoin, which is readily excreted by the kidneys. Even though there is a high production of allantoin from urate in cancer patients following rasburicase treatment, there are no studies on how allantoin excess could interfere with chemotherapy. We have evaluated allantoin interference with cisplatin efficiency on the lung cancer cell line H460 in vitro. The cells were treated with cisplatin (33 µM), with or without allantoin, for 48 h, in the presence or absence of UV light, and N-acetyl-L-cysteine (NAC) for 24 h. Cell viability, cell cycle, ROS production, apoptosis and immunoblot assays were performed. We showed that allantoin reduced the apoptosis induced by cisplatin in the H460 cell line. However, the activity of carboplatin and oxaliplatin, betulinic acid, TIBA, UV and H2O2 was not affected by allantoin. NMR spectroscopy showed that allantoin reduces cisplatin activity through direct interaction with cisplatin.

The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy. Several of these oncogenes have a negative impact on the main interferon antiviral defense, the double-stranded RNA-activated protein kinase (PKR), which helps viruses to spontaneously target tumor cells instead of normal cells. This review is focused on the negative impact of overexpression of oncogenes on conventional and targeted therapy and their positive impact on viral oncolysis due to their ability to inhibit PKR-induced translation blockage, allowing virion release and cell death.

Oncogenes are the primary candidates for target-directed therapy, given that they are involved directly in the progression and resistance of tumors. However, the appearance of point mutations can hinder the treatment of patients with these new molecules, raising costs and the need to development new analogs that target the novel mutations. Based on an analysis of homologies, the present study discusses the possibility of predicting the failure of a protein as a pharmacological target, due to its similarities with retrovirus sequences, which have extremely high mutation rates. This analysis was based on the molecular evidence available in the literature, and widely-used and well-established PSI-BLAST, with two iterations and maximum of 500 aligned sequences. The possibility of predicting which newly-discovered genes involved in tumor progression would likely result in the failure of targeted therapy, using free, simple and automated bioinformatics tools, could provide substantial savings in the time and financial resources needed for long-term drug development.