Uncontrolled Cellular Growth Research Articles

Genistein in focus: pharmacological effects and immune pathway modulation in cancer.

Cancer is a significant global health concern, responsible for mortality and morbidity of individuals. It is characterized by uncontrolled cellular growth, tumor formation, and potential metastasis. The immune system is pivotal in recognizing and eliminating cancerous cells, with immune cells such as T cells, B cells, natural killer cells (NK), and dendritic cells playing critical roles. Dysregulation of immune responses can contribute to cancer progression. Phytochemicals, bioactive compounds derived from plants, have gained attention for their potential roles in cancer prevention and therapy due to their antioxidant, anti-inflammatory, and immunomodulatory properties. Genistein, an isoflavone found in soy products, is of particular interest. In this study, genistein's mechanisms of action at the molecular and cellular levels in cancer were demonstrated, highlighting its impact on T and B lymphocytes, NK cells and dendritic cells. Genistein's ability to influence cytokine production, reducing levels of inflammatory cytokines such as TNF-α, IL-6, and IL-1β, is emphasized. Genistein modulates inflammatory response pathways like Toll-like receptors (TLRs), NF-κB, chemokines, and MAPK, inhibiting tumor growth, promoting apoptosis, and reducing metastasis. It shows promise in overcoming chemoresistance, particularly in ovarian and neuroblastoma cancers, by inhibiting autophagy. Genistein also affects T-cell execution markers, including granzyme B, TNF-α, and FAS ligand in cancer by influencing key proteins involved in immune response and apoptosis. Clinical trials have investigated genistein's therapeutic potential, revealing its promise in enhancing the efficacy of traditional cancer treatments while mitigating associated toxicities. Genistein helps overcome chemoresistance in various cancers by inhibiting autophagy and promoting apoptosis. It also enhances immunotherapy by boosting immune responses and modifying antigens, but careful dosing is needed when combined with anti-PD-1 treatments to avoid reducing effectiveness.

Drug Repurposing: Exploring Potential Anti-Cancer Strategies by Targeting Cancer Signalling Pathways.

The repurposing of previously clinically approved drugs as an alternative therapeutic approach to treating disease has gained significant attention in recent years. A multitude of studies have demonstrated various and successful therapeutic interventions with these drugs in a wide range of neoplastic diseases, including multiple myeloma, leukaemia, glioblastoma, and colon cancer. Drug repurposing has been widely encouraged due to the known efficacy, safety, and convenience of already established drugs, allowing the bypass of the long and difficult road of lead optimization and drug development. Repurposing drugs in cancer therapy is an exciting prospect due to the ability of these drugs to successfully target cancer-associated genes, often dysregulated in oncogenic signalling pathways, amongst which are the classical cancer signalling pathways; WNT (wingless-related integration type) and Hippo signalling. These pathways play a fundamental role in controlling organ size, tissue homeostasis, cell proliferation, and apoptosis, all hallmarks of cancer initiation and progression. Prolonged dysregulation of these pathways has been found to promote uncontrolled cellular growth and malignant transformation, contributing to carcinogenesis and ultimately leading to malignancy. However, the translation of cancer signalling pathways and potential targeted therapies in cancer treatment faces ongoing challenges due to the pleiotropic nature of cancer cells, contributing to resistance and an increased rate of incomplete remission in patients. This review provides analyses of a range of potential anti-cancer compounds in drug repurposing. It unravels the current understanding of the molecular rationale for repurposing these drugs and their potential for targeting key oncogenic signalling pathways.

Nano-Based Theranostics Approach in the Management of Cancer: Review.

Cancer is a prevalent and potentially fatal disease worldwide. The proliferation of abnormal cells and uncontrolled cellular growth characterizes cancer. Cancerous tumors exhibit distinct microenvironments characterized by a deficient lymphatic drainage system and aberrant blood supply. Various medications and diagnostic systems exist for cancer treatment, but they all have inherent limitations and undesirable consequences. Consequently, the achievement of effective cancer detection and treatment remains challenging. Theranostics nanoparticles are becoming increasingly popular in nano drug delivery systems. These nanoparticles can diagnose and treat tumors, making them a promising approach in the field. They are designed to be small in size, allowing them to be effective in delivering drugs to targeted areas. Furthermore, these nanoparticles can fundamentally transform the identification and management of several ailments, including cardiovascular disorders and infectious diseases. Such nanoparticles possess dual capabilities, functioning as therapeutic agents and diagnostic tools. They can transport medicinal substances, such as medications, nucleic acids, or therapeutic proteins, and include substances that can be used for imaging, such as contrast agents or fluorescent dyes, to enable non-invasive diagnostics and monitoring of the effectiveness of the treatment. These techniques can be employed for diagnostic purposes to identify, locate, and determine the extent of disorders using imaging modalities such as magnetic resonance imaging, computed tomography, positron emission tomography, and fluorescence imaging. These nanoparticles can deliver therapeutic compounds to specific locations accurately during therapy. This leads to improved effectiveness of the treatment, decreased adverse effects, and better patient outcomes. They offer a potential nanomedicine approach by providing diagnostic and therapeutic capabilities for disease diagnosis and treatment. Theranostics nanoparticles have distinct characteristics and adaptability, which can transform the healthcare sector by facilitating personalized and precise medical treatments.

Molecular Targeting of the BRAF Proto-Oncogene/Mitogen-Activated Protein Kinase (MAPK) Pathway across Cancers.

The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. Constitutive activation of this pathway by BRAF mutations can cause downstream activation of kinases, leading to uncontrolled cellular growth and carcinogenesis. Therefore, inhibition of BRAF and the downstream substrate MEK has been shown to be effective in controlling tumor growth and proliferation. Over the last decade, several BRAF and MEK inhibitors have been investigated, ranging from primarily melanoma to various cancer types with BRAF alterations. This subsequently led to several Food and Drug Administration (FDA) approvals for BRAF/MEK inhibitors for melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, histiocytosis neoplasms, and finally, tumor-agnostic indications. Here, this comprehensive review will cover the developments of BRAF and MEK inhibitors from melanomas to tumor-agnostic indications, novel drugs, challenges, future directions, and the importance of those drugs in personalized medicine.

A war on many fronts: cross disciplinary approaches for novel cancer treatment strategies.

Cancer is a disease characterized by uncontrolled cellular growth where cancer cells take advantage of surrounding cellular populations to obtain resources and promote invasion. Carcinomas are the most common type of cancer accounting for almost 90% of cancer cases. One of the major subtypes of carcinomas are adenocarcinomas, which originate from glandular cells that line certain internal organs. Cancers such as breast, prostate, lung, pancreas, colon, esophageal, kidney are often adenocarcinomas. Current treatment strategies include surgery, chemotherapy, radiation, targeted therapy, and more recently immunotherapy. However, patients with adenocarcinomas often develop resistance or recur after the first line of treatment. Understanding how networks of tumor cells interact with each other and the tumor microenvironment is crucial to avoid recurrence, resistance, and high-dose therapy toxicities. In this review, we explore how mathematical modeling tools from different disciplines can aid in the development of effective and personalized cancer treatment strategies. Here, we describe how concepts from the disciplines of ecology and evolution, economics, and control engineering have been applied to mathematically model cancer dynamics and enhance treatment strategies.

Pengaruh Progressive Muscle Relaxation (PMR) Terhadap Fatigue Pasien Kanker Payudara Yang Menjalani Kemoterapi

Breast cancer occurs due to abnormal, uncontrolled, and irregular cellular growth in the breast. The management of breast cancer includes surgery, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, and bone marrow manipulation. The physical impacts of chemotherapy include sleeping problems and fatigue. The non-pharmacological efforts to relieve this fatigue include progressive muscle relaxation (PMR). The research objective was to determine the effect of Progressive Muscle Relaxation (PMR) on the level of fatigue in breast cancer patients undergoing chemotherapy. The research design was a pre-experimental one group pre-posttest design. The population is breast cancer patients undergoing chemotherapy as many as 35 patients. The number of respondents is 35 respondents. The sampling technique used is total sampling. The research instrument used is the Fatigue Assessment Scale (FAS). The test used is the Wilcoxon test. The results showed that there was an effect of Progressive Muscle Relaxation (PMR) on the level of fatigue in breast cancer patients undergoing chemotherapy with a p value = 0.000 (<0.05). The research recommendation is Progressive Muscle relaxation (PMR) intervention as a non-pharmacological intervention to reduce the fatigue level of breast cancer patients undergoing chemotherapy in health services.

Evaluating the Molecular Properties and Function of ANKHD1, and Its Role in Cancer.

Ankyrin repeat and single KH domain-containing protein 1 (ANKHD1) is a large, scaffolding protein composed of two stretches of ankyrin repeat domains that mediate protein-protein interactions and a KH domain that mediates RNA or single-stranded DNA binding. ANKHD1 interacts with proteins in several crucial signalling pathways, including receptor tyrosine kinase, JAK/STAT, mechanosensitive Hippo (YAP/TAZ), and p21. Studies into the role of ANKHD1 in cancer cell lines demonstrate a crucial role in driving uncontrolled cellular proliferation and growth, enhanced tumorigenicity, cell cycle progression through the S phase, and increased epithelial-to-mesenchymal transition. Furthermore, at a clinical level, the increased expression of ANKHD1 has been associated with greater tumour infiltration, increased metastasis, and larger tumours. Elevated ANKHD1 resulted in poorer prognosis, more aggressive growth, and a decrease in patient survival in numerous cancer types. This review aims to gather the current knowledge about ANKHD1 and explore its molecular properties and functions, focusing on the protein's role in cancer at both a cellular and clinical level.

Molecular pathways and therapeutic targets linked to triple-negative breast cancer (TNBC).

Cancer is a group of diseases characterized by uncontrolled cellular growth, abnormal morphology, and altered proliferation. Cancerous cells lose their ability to act as anchors, allowing them to spread throughout the body and infiltrate nearby cells, tissues, and organs. If these cells are not identified and treated promptly, they will likely spread. Around 70% of female breast cancers are caused by a mutation in the BRCA gene, specifically BRCA1. The absence of progesterone, oestrogen and HER2 receptors (human epidermal growth factor)distinguishes the TNBC subtype of breast cancer. There were approximately 6,85,000 deaths worldwide and 2.3 million new breast cancer cases in women in 2020. Breast cancer is the most common cancer globally, affecting 7.8 million people at the end of 2020. Compared to other cancer types, breast cancer causes more women to lose disability-adjusted life years (DALYs). Worldwide, women can develop breast cancer at any age after puberty, but rates increase with age. The maintenance of mammary stem cell stemness is disrupted in TNBC, governed by signalling cascades controlling healthy mammary gland growth and development. Interpreting these essential cascades may facilitate an in-depth understanding of TNBC cancer and the search for an appropriate therapeutic target. Its treatment remains challenging because it lacks specific receptors, which renders hormone therapy and medications ineffective. In addition to radiotherapy, numerous recognized chemotherapeutic medicines are available as inhibitors of signalling pathways, while others are currently undergoing clinical trials. This article summarizes the vital druggable targets, therapeutic approaches, and strategies associated with TNBC.

Skin Cancer: The Ozone Layer and UV Radiation

The ozone layer is a thin, invisible layer that protects life on earth. It is made up of several ozone molecules that are recreated and destroyed by ultraviolet radiation from the sun. Ultraviolet radiation, commonly known as UV radiation, is not visible to the human eye and exhibits wavelengths from 10 to 400 nm. UV radiation has three types: UVA, UVB, and UVC. The ozone layer completely absorbs UVC, mostly absorbs UVB, and slightly absorbs UVA. UVB and UVA radiation are the primary non-genetic factors for skin cancer and disease. UV radiation causes DNA damage, resulting in uncontrolled cellular growth of cancerous cells and mutations. Types of skin cancer are divided into melanoma and nonmelanoma. Both are commonly marked by abnormal formations on the skin. This research paper uses statistics and data on the ozone layer, UVR, and skin cancer to highlight the correlation between these three factors. The ozone layer directly affects the penetration of UVR into the atmosphere; UVR directly affects the generation of skin cancer. Therefore, our study demonstrates that the relationship between the ozone layer and UVR exposure is vital to preventing skin cancer.

PIK3CAMutations in Breast Cancer Subtypes Other Than HR-Positive/HER2-Negative.

The phosphoinositide 3-kinase (PI3K) pathway plays a key role in cancer, influencing growth, proliferation, and survival of tumor cells. PIK3CA mutations are generally oncogenic and responsible for uncontrolled cellular growth. PI3K inhibitors (PI3Ki) can inhibit the PI3K/AKT/mTOR pathway, although burdened by not easily manageable toxicity. Among PI3Ki, alpelisib, a selective p110α inhibitor, is approved for the treatment of hormone receptor (HR)+/HER2- PIK3CA mutant metastatic breast cancer (BC) that has progressed to a first line endocrine therapy. PIK3CA mutations are also present in triple negative BC (TNBC) and HER2+ BC, although the role of PI3K inhibition is not well established in these subtypes. In this review, we go through the PI3K/AKT/mTOR pathway, describing most common mutations found in PI3K genes and how they can be detected. We describe the available biological and clinical evidence of PIK3CA mutations in breast cancers other than HR+/HER2-, summarizing clinical trials investigating PI3Ki in these subtypes.

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure-activity relationship, and mechanisms of action (2019-2021).

Cancer, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth, remains a prominent cause of death across the world. Almost all currently available anticancer agents used in clinical practice have developed multidrug resistance, creating an urgent need to develop novel chemotherapeutics. Benzimidazole derivatives could exertanticancer properties through diverse mechanisms, inclusive of the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, antiangiogenesis, and blockage of glucose transport. Moreover, several benzimidazole-based agents have already been approved for the treatment of cancers. Hence, benzimidazole derivatives are useful scaffolds for the development of novel anticancer agents. In particular, benzimidazole hybrids could exert dual or multiple antiproliferative activities and had the potential to overcome drug resistance, demonstrating the potential of benzimidazole hybrids as potential prototypes for clinical deployment in the control and eradication of cancers. The purpose of the present review article is to provide a comprehensive landscape of benzimidazole hybrids as potential anticancer agents, and the structure-activity relationship as well as mechanisms of action are also discussed to facilitate the further rational design of more effective candidates, covering articles published from 2019 to 2021.

Investigation of Cinnamaldehyde Derivatives as Potential Organic UV Filters

Long-term exposure to ultraviolet (UV) rays has been attributed to irreversible health defects at the cellular level. Most importantly, damage to DNA by UVA and UVB rays can result in uncontrolled cellular growth, leading to skin cancer. As a result, topical treatments have been developed over time to protect the skin from UVA and UVB rays. The active ingredients in sunscreens or sun creams are sometimes unsaturated, aromatic organic compounds capable of absorbing harmful UV photons at a great range of wavelengths. Absorption capabilities of these species depend on their degree of conjugation and their molar absorptivity. With this knowledge, two cinnamaldehyde derivatives were synthesized into five potential organic UV filters by the aldol condensation reaction. The products were identified using nuclear magnetic resonance (NMR) and attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopies, and ultraviolet-visible (UV-vis) spectroscopy was used to determine the UV absorption range and intensity of absorption for each compound. Since the compounds would hypothetically be utilized in topical ointments to aide in skin protection, these compounds were assessed in the presence of Pseudomonas aeruginosa, a representative bacterium of the skin’s natural flora. A time-course assay was conducted to detect growth effects of P. aeruginosa in the presence of the organic compounds. According to the spectroscopic and bacterial analyses of these UV-blocking compounds, three compounds were determined to be potential UV filters that cover UVA region while demonstrating no apparent harm to the natural skin bacteria P. aeruginosa, while the other two likely diminished bacterial growth by simple niche inhibition.

Discovery of New Imidazo[2,1-b]thiazole Derivatives as Potent Pan-RAF Inhibitors with Promising In Vitro and In Vivo Anti-melanoma Activity.

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives possessing a terminal sulfonamide moiety were synthesized. Pan-RAF inhibitory effect of the new series was investigated, and structure-activity relationship is discussed. Antiproliferative activity of the target compounds was tested against the NCI-60 cell line panel. The most active compounds were further tested to obtain their IC50 values against cancer cells. Compound 27c with terminal open chain sulfonamide and 38a with a cyclic sulfamide moiety showed the highest activity in enzymatic and cellular assay, and both compounds were able to inhibit phosphorylation of MEK and ERK. Compound 38a was selected for testing its in vivo activity against melanoma. Cellular and animal activities are reported.

The Association between Cyclin D1 (CCND1) rs9344 AA Genotype and Increased Risk of Colorectal Cancer in An Iranian Population

Background: Colorectal cancer (CRC) is a globally growing disease with a steady decrease in the age of incidence. Pathogenesis of this cancer stems from a complex interaction between environmental factors and genetic predisposition. Among genetic factors, high activity of cyclin D1gene is prominent. A polymorphism (G870A) in exon 4 of cyclin D1 is responsible for a variant transcript with longer half-life and may culminate in uncontrollable cellular growth, thereby contributing to cancer development. Method: This case-control study evaluated the frequency of CCND1 G870A polymorphism and risk of sporadic CRC in an Iranian population. The study population comprised 50 CRC patients and 50 CRC-free controls selected on the basis of colonoscopy examination. For genotyping, we performed polymerase chain reaction – restriction fragment length polymorphism analysis (PCR-RFLP). Result: AA genotype frequencies compared to GA+GG genotype frequencies between cases and controls showed that AA genotype frequency in the case group was significantly higher than the control group (AA vs. GG + GA: OR= 2.25, 95% CI: 1.13-5.54, P=0.04). Allele A frequency was 57% in patients and 46% in healthy subjects. Statistical analysis showed that the odds ratio of carriers with allele A for risk of CRC was 1.55 more than G allele carriers (OR=1.55, 95% CI: 0.856-2.828). Moreover, physical activity in cases was significantly less than controls (P=0.001). We further observed that the subjects in the case group used fewer non-steroidal antiinflammatory drugs compared to healthy controls (P=0.02). Analysis of body mass index (BMI) between cases and controls revealed that the average of BMI in cases was higher than the controls (P =0.04). Conclusion: Our results showed that individuals carrying the AA genotype ran a higher risk of developing CRC compared to GG genotype.

Oral Squamous Cell Carcinoma and the Cutting Edge of Nanotechnology

Introduction: Cancer is a group of diseases characterized by uncontrolled cellular growth or proliferation. Oral squamous cell carcinoma (OSCC) is a group of cancers mainly affecting the buccal cavity and associated area, with high rate of mortality and morbidity. Chronic consumption of alcohol, both smoking and smokeless tobacco, and betel quid are considered as the prominent determinants for the initiation and development of OSCC. The current treatment strategy of OSCC is associated with the common side effects of non-specific anticancer drug delivery. In addition, the treatment also deals with the recurrence of OSCC after completion of the therapy, which is responsible for its high mortality rate. Nanotechnology is an emerging discipline in drug delivery, disease diagnosis, and imaging. Nanoparticles are a group of colloidal carriers with approximately 1-1000 nm size range. Nanoparticles, due to large surface area to volume ratio, display different physicochemical characteristics favorable for their use in chemotherapy. The nanoparticles with options for modifications in theirsizes, surface charges, drug payload, and drug bioavailability can be used as a drug delivery system. The dynamic and flexible nature of nanoparticles can be employed to both active and passive targeting of cancer cells combating the usual side effects as well as other complexities associated with the conventional chemotherapy. Conclusions: The nanoparticles can be regarded as the future of drug delivery in cancer therapy.

RETRACTED ARTICLE: Down-regulated lncRNA DLX6-AS1 inhibits tumorigenesis through STAT3 signaling pathway by suppressing CADM1 promoter methylation in liver cancer stem cells

BackgroundLiver cancer stem cells (LCSCs) are a small subset of cells characterized by unlimited self-renewal, cell differentiation, and uncontrollable cellular growth. LCSCs are also resistant to conventional therapies and are thus believed to be held responsible for causing treatment failure of hepatocellular carcinoma (HCC). It has been recently found that long non-coding RNAs (lncRNAs) are important regulators in HCC. This present study aims to explore the underlying mechanism of how lncRNA DLX6-AS1 influences the development of LCSCs and HCC.MethodsA microarray-based analysis was performed to initially screen differentially expressed lncRNAs associated with HCC. We then analyzed the lncRNA DLX6-AS1 levels as well as CADM1 promoter methylation. The mRNA and protein expression of CADM1, STAT3, CD133, CD13, OCT-4, SOX2, and Nanog were then detected. We quantified our results by evaluating the spheroid formation, proliferation, and tumor formation abilities, as well as the proportion of tumor stem cells, and the recruitment of DNA methyltransferase (DNMT) in LCSCs when lncRNA DLX6-AS1 was either overexpressed or silenced.ResultsLncRNA DLX6-AS1 was upregulated in HCC. The silencing of lncRNA DLX6-AS1 was shown to reduce and inhibit spheroid formation, colony formation, proliferation, and tumor formation abilities, as well as attenuate CD133, CD13, OCT-4, SOX2, and Nanog expression in LCSCs. Furthermore, downregulation of lncRNA DLX6-AS1 contributed to a reduction in CADM1 promoter methylation via suppression of DNMT1, DNMT3a, and DNMT3b in LCSCs and inactivating the STAT3 signaling pathway.ConclusionThis study demonstrated that down-regulated lncRNA DLX6-AS1 may inhibit the stem cell properties of LCSCs through upregulation of CADM1 by suppressing the methylation of the CADM1 promoter and inactivation of the STAT3 signaling pathway.

A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation.

TPS3161 Background: RAS proteins are part of the family of small GTPases which regulate intracellular signaling pathways responsible for cell growth, migration, survival and differentiation. Oncogenic point mutations in RAS in codons 12, 13, and 61 occur in up to one-third of all human cancers and result in constitutive activation of RAS signaling, playing a key role in uncontrolled cellular growth and malignant transformation. Mutant KRASG12C in particular comprises approximately 14% of lung adenocarcinoma and 4% of colon adenocarcinoma, and less commonly in certain other types of cancer. For decades, KRAS was considered undruggable due to its high affinity for GTP/GDP and the lack of a clear binding pocket. Recent discoveries have enabled the development of compounds, including MRTX849, that covalently bind to KRASG12C at the cysteine at residue 12, lock the protein in its inactive GDP-bound conformation, and inhibit KRAS-dependent signal transduction. MRTX849 is a potent, orally-available, mutation-selective small molecule covalent inhibitor of KRASG12C. MRTX849 inhibits KRASG12C signaling in cell lines harboring this mutation, and results in tumor regression in a broad spectrum of KRASG12C animal models. Methods: This multi-center, Phase 1/2, multiple expansion cohort trial evaluates the safety, pharmacokinetics (PK), metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumor malignancies with a KRAS (p.G12C) mutation. The study starts with an evaluation of dose and regimen of MRTX849 using a combination of the accelerated titration and modified toxicity probability interval designs, with MRTX849 initially administered once daily in a continuous regimen expressed in 3-week cycles. As potentially viable regimens are identified, Phase 1b expansion cohorts will be opened to provide greater safety and PK data for determination of the recommended Phase 2 dose (RP2D) and regimen. In Phase 2, separate cohorts of patients by histological diagnosis, including non-small cell lung cancer, colorectal, and other solid tumors, will be enrolled and evaluated for clinical activity using a predictive probability design. The study is open for enrollment, and recruitment is ongoing. Clinical trial information: NCT03785249.

MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation.

SummaryThe MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.

Dietary Fat and Sugar in Promoting Cancer Development and Progression

The uncontrolled cellular growth that characterizes tumor formation requires a constant delivery of nutrients. Since the 1970s, researchers have wondered if the supply of nutrients from the diet could impact tumor development. Numerous studies have assessed the impact of dietary components, specifically sugar and fat, to increased cancer risk. For the most part, data from these trials have been inconclusive; however, this does not indicate that dietary factors do not contribute to cancer progression. Rather, the dietary contribution may be dependent on tumor, patient, and context, making it difficult to detect in the setting of large trials. In this review, we combine data from prospective cohort trials with mechanistic studies in mice to argue that fat and sugar can play a role in tumorigenesis and disease progression. We find that certain tumors may respond directly to dietary sugar (colorectal and endometrial cancers) and fat (prostate cancer) or indirectly to the obese state (breast cancer).

Staurosporine induces apoptosis in pancreatic carcinoma cells PaTu 8988t and Panc-1 via the intrinsic signaling pathway

BackgroundCancer, one of the leading causes of death worldwide, develops when the normal balance between mitosis and apoptosis is disrupted. The subsequently increased proliferation rate or decreased apoptosis rate of cells leads to uncontrolled cellular growth. Thus, the current aim of cancer research is to increase the apoptosis rate in tumor cells—while limiting the concurrent death of healthy cells—and to induce controlled apoptosis in abnormal cells. Staurosporine is a very potent inducer of apoptosis because it inhibits many different kinases. So far, many different kinase pathways of staurosporine-induced apoptosis have been discussed for various tumor entities.AimsTo identify the effect of staurosporine in pancreatic and colorectal carcinoma cells and its apoptosis-inducing signaling pathway.MethodsThe apoptosis rate in pancreatic and colorectal carcinoma cells was analyzed by annexin V staining after staurosporine administration. Staurosporine stimulation and its effects on the expression of Bcl2, BAX, Bad, caspase-8, and caspase-9 were investigated with immunoblot.ResultsStaurosporine significantly increased apoptosis in pancreatic carcinoma cells. Western blot analysis showed activation of caspase-9 in PaTu 8988t and Panc-1 cells with 1 µM staurosporine. In addition, expression of Bcl2 and Bad was decreased in PaTu 8988t cells. In colorectal carcinoma cells SW 480, staurosporine stimulation did not induce apoptosis.ConclusionModern therapeutic strategies for tumor diseases target the efficient modulation of specific signaling and transcription pathways. In this respect, the therapeutic potential of protein kinase inhibitors has been repeatedly discussed. Our study showed that staurosporine induces apoptosis in pancreatic carcinoma cells via the intrinsic signaling pathway. Thus, staurosporine is a suitable positive control for in vitro apoptosis tests for the pancreatic cancer cell lines PaTu 8988t and Panc-1. Further clinical studies should analyze the impact of this finding on cancer treatment.