Epigenetics Linked to Resistance for Anti-Cancer Drug

BACKGROUND: Regenerating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanisms in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism. AIM: To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance. METHODS: We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC...

Breast cancer is the leading cause of death among women worldwide, and certain subtypes are highly aggressive and drug resistant. As oxidative stress is linked to the onset and progression of cancer, new alternative therapies, based on plant-derived compounds that activate signaling pathways involved in the maintenance of cellular redox homeostasis, have received increasing interest. Among the bioactive dietary compounds considered for cancer prevention and treatment are flavonoids, such as quercetin, carotenoids, such as lycopene, polyphenols, such as resveratrol and stilbenes, and isothiocyanates, such as sulforaphane...

BACKGROUND: The combination of Programmed Cell Death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) blockade has dramatically improved the overall survival rate for malignant melanoma. Immune checkpoint blockers (ICBs) limit the tumor's immune escape yet only for approximately a third of all tumors and, in most cases, for a limited amount of time. Several approaches to overcome resistance to ICBs are being investigated among which the addition of epigenetic drugs that are expected to act on both immune and tumor cells...

Colorectal cancer (CRC) is one of the leading malignant diseases worldwide with a high rate of metastasis and poor prognosis. Treatment options include surgery, which is usually followed by chemotherapy in advanced CRC. With treatment, cancer cells could become resistant to classical cytostatic drugs such as 5-fluorouracil (5-FU), oxaliplatin, cisplatin, and irinotecan, resulting in chemotherapeutic failure. For this reason, there is a high demand for health-preserving re-sensitization mechanisms including the complementary use of natural plant compounds...

It has been proven that metastatic recurrence and therapeutic resistance are linked. Due to the variability of individuals and tumors, as well as the tumor's versatility in avoiding therapies, therapy resistance is more difficult to treat. Therapy resistance has significantly restricted the clinical feasibility and efficacy of tumor therapy, despite the discovery of novel compounds and therapy combinations with increasing efficacy. In several tumors, lysine specific demethylase 1 (LSD1) has been associated to metastatic recurrence and therapeutic resistance...

Melanoma is a deadly form of cancer characterized by remarkable therapy resistance. Analyzing the transcriptome of MAPK inhibitor sensitive- and resistant-melanoma, we discovered that APAF-1 is negatively regulated by MITF in resistant tumors. This study identifies the MITF/APAF-1 axis as a molecular driver of MAPK inhibitor resistance. A drug-repositioning screen identified quinacrine and methylbenzethonium as potent activators of apoptosis in a context that mimics drug resistance mediated by APAF-1 inactivation...

N6 -methyladenosine (m6 A), the newest and most prevalent layer of internal epigenetic modification in eukaryotic mRNA, has been demonstrated to play a critical role in cancer biology. Increasing evidence has highlighted that the interaction between cancer stem cells (CSCs) and the tumor immune microenvironment (TIME) is the root cause of tumorigenesis, metastasis, therapy resistance, and recurrence. In recent studies, the m6 A modification has been tightly linked to this CSC-TIME interplay, participating in the regulation of CSCs and TIME remolding...

Cancer is a complex disease and cancer development takes 10-50 years involving epigenetics. Evidence suggests that approximately 80% of human cancers are linked to environmental factors impinging upon genetics/epigenetics. Because advanced metastasized cancers are resistant to radiotherapy/chemotherapeutic drugs, cancer prevention by relatively nontoxic chemopreventive "epigenetic modifiers" involving epigenetics/epigenomics is logical. Isothiocyanates are relatively nontoxic at low nutritional and even higher pharmacologic doses, with good oral bioavailability, potent antioxidative stress/antiinflammatory activities, possess epigenetic-modifying properties, great anticancer efficacy in many in vitro cell culture and in vivo animal models...

BACKGROUND: The acquisition of resistance to chemotherapy is a major hurdle in the successful application of cancer therapy. Several anticancer approaches, including chemotherapies, radiotherapy, surgery and targeted therapies are being employed for the treatment of cancer. However, cancer cells reprogram themselves in multiple ways to evade the effect of these therapies, and over a period of time, the drug becomes inactive due to the development of multi-drug resistance (MDR). MDR is a complex phenomenon where malignant cells become insensitive to anticancer drugs and attain the ability to survive even after several exposures of anticancer drugs...

Breast cancer is a frequently occurring malignancy in women. Immunologically, breast cancers can be classified into four subtypes depending on the types of receptors present and their expression profiles. These are estrogen positive, progesterone positive, human epidermal growth factor receptor type 2 (HER2) positive, and triple-negative as identified by immunohistochemistry. This classification is the basis of response to treatment, prognosis, and survival. With the identification of HER2 receptor overexpression, targeted therapies with anti-HER2 agents have been developed...

Schlafen 11 (SLFN11) sensitizes cells to a broad range of anti-cancer drugs including platinum derivatives (cisplatin and carboplatin), inhibitors of topoisomerases (irinotecan, topotecan, doxorubicin, daunorubicin, mitoxantrone and etoposide), DNA synthesis inhibitors (gemcitabine, cytarabine, hydroxyurea and nucleoside analogues), and poly(ADPribose) polymerase (PARP) inhibitors (olaparib, rucaparib, niraparib and talazoparib). In spite of their different primary mechanisms of action, all these drugs damage DNA during S-phase, activate the intra-S-phase checkpoint and induce replication fork slowing and stalling with single-stranded DNA segments coated with replication protein A...

Background: In many cases of breast cancer, the aberrant methylation of TP53 gene leads to uncontrolled cell proliferation and apoptosis inhibition. Moreover, expression of oncogenes which are under the control of P53 protein could be altered. Survivin as a conspicuous example of this category plays important roles in tumorigenesis, drug resistance and apoptosis inhibition. The present study was done to reveal the effects of Scrophularia atropatana extract on epigenetic situation of TP53 gene promoter and the expression levels of anti-apoptotic gene, survivin and its potential for production of cancer epi-drugs...

Metabolic alterations, driven by genetic and epigenetic factors, have long been known to be associated with the etiology of cancer. Furthermore, accumulating evidence suggest that cancer metabolism is intimately linked to drug resistance, which is currently one of the most important challenges in cancer treatment. Altered metabolic pathways help cancer cells to proliferate at a rate higher than normal, adapt to nutrient limited conditions, and develop drug resistance phenotypes. Application of systems biology, boosted by recent advancement of novel high-throughput technologies to obtain cancer-associated, transcriptomic, proteomic and metabolomic data, is expected to make a significant contribution to our understanding of metabolic properties related to malignancy...

Cancer stem cells (CSCs) are rare, tumour-initiating cells that exhibit stem cell properties: capacity of self-renewal, pluripotency, highly tumorigenic potential, and resistance to therapy. Cancer stem cells have been characterised and isolated from many cancers, including breast cancer. Developmental pathways, such as the Wnt/β-catenin, Notch/γ-secretase/Jagged, Shh (sonic hedgehog), and BMP signalling pathways, which direct proliferation and differentiation of normal stem cells, have emerged as major signalling pathways that contribute to the self-renewal of stem and/or progenitor cells in a variety of organs and cancers...

Non-Small Cell Lung Cancer (NSCLC) remains an aggressive and fatal disease with low responsiveness to chemotherapy, frequent drug resistance development and metastatic behavior. Platinum-based therapy is the standard of care for NSCLC with limited benefits. Since epigenetic alterations have been implicated in the aggressive behavior of lung cancer, the purpose of the present study was to examine the capability of the pan-histone deacetylase inhibitor SAHA and of ST3595, a novel hydroxamate-based compound, to interfere with the proliferative and invasive potential of NSCLC cells...

BACKGROUND/AIM: Mucin 4 (MUC4) has been linked to resistance to gemcitabine in pancreatic cancer cells. The aim of the present study was to assess whether epigenetic control of MUC4 expression can sensitize pancreatic cancer cells to gemcitabine treatment. MATERIALS AND METHODS: A 76-member combined epigenetics and phosphatase small-molecule inhibitor library was screened for anti-proliferative activity against the MUC4(+) gemcitabine-resistant pancreatic cancer cell line Capan-1, followed by high-content screening of protein expression...

The interplay of metabolism and epigenetic regulatory mechanisms has become a focal point for a better understanding of cancer development and progression. In this study, we have acquired data supporting previous observations that demonstrate glutamine metabolism affects histone modifications in human breast cancer cell lines. Treatment of non-invasive epithelial (T-47D and MDA-MB-361) and invasive mesenchymal (MDA-MB-231 and Hs-578T) breast cancer cell lines with the glutaminase inhibitor, Compound 968, resulted in cytotoxicity in all cell lines, with the greatest effect being observed in MDA-MB-231 breast cancer cells...

Although the prognosis of acute lymphoblastic leukemia (ALL) has improved considerably in recent years, some of the cases still exhibit therapy-resistant. We have previously reported that CD9 was expressed heterogeneously in B-ALL cell lines and CD9(+) cells exhibited an asymmetric cell division with greater tumorigenic potential than CD9(-) cells. CD9(+) cells were also serially transplantable in immunodeficient mice, indicating that CD9(+) cell possess self-renewal capacity. In the current study, we performed more detailed analysis of CD9 function for the cancer stem cell (CSC) properties...

Human cancer can arise due to inherited and sporadic genetic and epigenetic changes. These changes consequently inhibit the function of tumor suppressors and pro-apoptotic genes, while activate oncogenes. Most human cancers arise as benign tumors; after acquiring additional genetic and epigenetic changes, they become malignant and eventually metastasize to distal organs. Recent studies have implicated multiple tumor suppressing mechanisms that prevent neoplastic transformation and thus have anti-cancer activities...