Modulation of Apoptosis in Colon Cancer Cells by Bioactive Compounds

A big challenge for a successful colon cancer treatment is the lack of eradication of the entire tumour cell population and consequent development of chemoresistance. Control of cell number from tissues and elimination of cells predisposed to malignant transformation, having an aberrant cell cycle or presenting DNA mutations, might be performed by a cellular ‘suicide’ mechanism — the programmed cell death, or apoptosis. Coordinated activation and execution of multiple subprograms are needed, added by a good knowledge of the basic components of the death machinery, besides their interaction to regulate apoptosis in a coordinated manner. Triggering apoptosis in target cells is a key mechanism by which chemotherapy promotes cell killing. Many anti‐cancer drugs act during physiological pathways of apoptosis, leading to tumour cell destruction. New therapeutic approaches in cancer induce tumour cells to undergo apoptosis and break the cancer cell resistance to apoptosis commands. Administrations of natural compounds that prevent induction, inhibit or delay the progression of cancer, or induce inhibition or reversal of carcinogenesis at a premalignant stage represent chemoprevention strategies. Several natural compounds have been shown to be promising based on their anti‐cancer effects and low toxicity; alternative approaches might be taken into account to obtain a stronger anti‐tumour response when lower concentrations of anti‐cancer drugs are used, and to diminish the undesirable side‐effects

Interplay of Epigenetics with Gynecological Cancer

Recent data on the cell deregulation that occurs during the progression to cancer underlines the cooperation between genetic and epigenetic alterations leading to a malignant phenotype. Unlike genetic alterations, the epigenetic changes do not affect the DNA sequence of the genes, but determine the regulation of gene expression acting upon the genome. Moreover, unlike genetic changes, epigenetic ones are reversible, making them therapeutic targets in various conditions in general and in cancer disease in particular. The term epigenetics includes a series of covalent modifications that regulate the methylation pattern of DNA and posttranslational modifications of histones. Gene expression can also be regulated at the posttranscriptional level by microRNAs (miRNAs), a family of small noncoding RNAs that inhibit the translation of mRNA to protein. miRNAs can act as ‘oncomiRs’, as tumor suppressors, or both. In this chapter, we will (1) summarize the current literature on the key processes responsible for epigenetic regulation: DNA methylation, histone modifications and posttranscriptional gene regulation by miRNAs; (2) evaluate aberrant epigenetic modifications as essential players in cancer progression; (3) establish the roles of microenvironment-mediated epigenetic perturbations in the development of gynecological neoplasia; (4) evaluate epigenetic factors involved in drug resistance

Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

BCR-ABL1-negative myeloproliferative neoplasms are classically represented by primary myelofibrosis, polycythemia vera, and essential thrombocythemia. These entities are stem cell-derived clonal disorders characterized by hematopoietic progenitor autonomy or hypersensitivity to cytokines, most of them presenting mutations in Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL). Deregulation of pro- and antiapoptotic genes is also claimed as an important mechanism involved in cell resistance to cell death and accumulation of myeloid cells in myeloproliferative neoplasms. Apoptosis, as one of the best-characterized types of programmed cell death, has a clear role in hematopoiesis control. However, the exact pathways affected in BCR-ABL1-negative myeloproliferative neoplasms have not yet been fully clarified. This chapter will explore the modifications affecting programmed cell death pathways involved in myeloid proliferation and how these alterations might be exploited in single or combined targeted therapeutic strategies

Induction of differentiation inhibits the tumorigenic potential of glioblastoma cancer stem cells

The outcome of the patients with newly diagnosed glioblastoma remains dismal, despite the use of surgery, radiotherapy and adjuvant temozolomide and while new agents like anti-angiogenic agents seem to offer some promise, a new approach is needed. Recent studies suggest that cancer stem cells (CSCs) may play an important role in malignant gliomas invasion and proliferation. Therefore, CSCs became new therapeutical targets, and one of the main experimental therapies which could be used against CSCs is the differentiation therapy.The purpose of this study was to characterize the CSCs isolated from glioblastoma samples, to assess in vivo the tumorigenic potential of these cells and to induct the differentiation of the CSCs. The changes in invasive markers (matrixmetalloproteases-MMPs, cadherins and cathenins) expression were assessed. CSCs exposed to differentiation inductor factors have been inoculated in nude mice and their tumorigenic potential has been evaluated. The stemness biological feature was correlated with increased of MMPs, cadherins, catenin expression and with tumour contra-lateral invasion. The expression of MMPs, cadherins and cadherins decreased after exposure of the CSCs cultures to the differentiation inductor factors. In vivo experiments demonstrated the inhibition of tumorigenic potential of differentiated CSCs cultures.In conclusion, differentiated CSCs showed a decreased expression of invasive markers in vitro and lost their tumorigenic potential in vivo

Common themes in antimicrobial and anticancer drug resistance

Publication history: Accepted - 22 July 2022; Published - 8 August 2022.Antimicrobial and anticancer drug resistance represent two of the main global challenges for the public health, requiring immediate practical solutions. In line with this, we need a better understanding of the origins of drug resistance in prokaryotic and eukaryotic cells and the evolutionary processes leading to the occurrence of adaptive phenotypes in response to the selective pressure of therapeutic agents. The purpose of this paper is to present some of the analogies between the antimicrobial and anticancer drug resistance. Antimicrobial and anticancer drugs share common targets and mechanisms of action as well as similar mechanisms of resistance (e.g., increased drug efflux, drug inactivation, target alteration, persister cells’ selection, protection of bacterial communities/malignant tissue by an extracellular matrix, etc.). Both individual and collective stress responses triggered by the chemotherapeutic agent involving complex intercellular communication processes, as well as with the surrounding microenvironment, will be considered. The common themes in antimicrobial and anticancer drug resistance recommend the utility of bacterial experimental models for unraveling the mechanisms that facilitate the evolution and adaptation of malignant cells to antineoplastic drugs.This research was funded by CNFIS-FDI-2022-0675, UEFISCDI - PN-III-P4-PCE2021-1797, PN-III-P1-1.1-36PD-2019- 0499, Grant number 224/2021 and the Ministry of Research, Innovation, and Digitalization through Program 1—Development of the national R&D system, Subprogram 1.2—Institutional performance—Financing projects for excellence in RDI, Contract no. 41 PFE/30.12.2021

Implications of oral dysbiosis and HPV infection in head and neck cancer: from molecular and cellular mechanisms to early diagnosis and therapy

Head and neck cancer (HNC) is the sixth most common type of cancer, with more than half a million new cases annually. This review focuses on the role of oral dysbiosis and HPV infection in HNCs, presenting the involved taxons, molecular effectors and pathways, as well as the HPV-associated particularities of genetic and epigenetic changes and of the tumor microenvironment occurred in different stages of tumor development. Oral dysbiosis is associated with the evolution of HNCs, through multiple mechanisms such as inflammation, genotoxins release, modulation of the innate and acquired immune response, carcinogens and anticarcinogens production, generation of oxidative stress, induction of mutations. Thus, novel microbiome-derived biomarkers and interventions could significantly contribute to achieving the desideratum of personalized management of oncologic patients, regarding both early diagnosis and treatment. The results reported by different studies are not always congruent regarding the variations in the abundance of different taxons in HNCs. However, there is a consistent reporting of a higher abundance of Gram-negative species such as Fusobacterium, Leptotrichia, Treponema, Porphyromonas gingivalis, Prevotella, Bacteroidetes, Haemophilus, Veillonella, Pseudomonas, Enterobacterales, which are probably responsible of chronic inflammation and modulation of tumor microenvironment. Candida albicans is the dominant fungi found in oral carcinoma being also associated with shorter survival rate. Specific microbial signatures (e.g., F. nucleatum, Bacteroidetes and Peptostreptococcus) have been associated with later stages and larger tumor, suggesting their potential to be used as biomarkers for tumor stratification and prognosis. On the other hand, increased abundance of Corynebacterium, Kingella, Abiotrophia is associated with a reduced risk of HNC. Microbiome could also provide biomarkers for differentiating between oropharyngeal and hypopharyngeal cancers as well as between HPV-positive and HPV-negative tumors. Ongoing clinical trials aim to validate non-invasive tests for microbiome-derived biomarkers detection in oral and throat cancers, especially within high-risk populations. Oro-pharyngeal dysbiosis could also impact the HNCs therapy and associated side-effects of radiotherapy, chemotherapy, and immunotherapy. HPV-positive tumors harbor fewer mutations, as well as different DNA methylation pattern and tumor microenvironment. Therefore, elucidation of the molecular mechanisms by which oral microbiota and HPV infection influence the HNC initiation and progression, screening for HPV infection and vaccination against HPV, adopting a good oral hygiene, and preventing oral dysbiosis are important tools for advancing in the battle with this public health global challenge