pH-responsive targeted nanoparticles release ERK-inhibitor in the hypoxic zone and sensitize free gemcitabine in mutant K-Ras-addicted pancreatic cancer cells and mouse model.

Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Therefore, despite suboptimal clinical effects, gemcitabine (GEM) remains the first-line chemotherapeutic drug in the clinic for PDAC treatment. The therapeutic limitations of GEM are primarily due to poor bioavailability and the development of chemoresistance resulting from the addiction of mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic barriers with a hypoxic microenvironment.

Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers.

The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleoside antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with the inhibition of cancer cell growth and progression of tumors.

Report on the 11th international workshop on the CCN family of genes, Nice, October 20-24, 2022.

In celebration of the twentieth anniversary of the inception of the CCN society, and of the first post-Covid-19 live meeting, the executive board of the ICCNS had chosen Nice as the venue for the 11th International workshop on the CCN family of genes. On this occasion participation in the meeting was extended to colleagues from other cell signaling fields who were invited to present both an overview of their work and the future directions of their laboratory. Also, for the first time, the members of the JCCS Editorial Board were invited to participate in a JCCS special session during which all aspects of the journal « life » were addressed and opened to free critical discussion.

The role of CCNs in controlling cellular communication in the tumor microenvironment.

The Cellular communication network (CCN) family of growth regulatory factors comprises six secreted matricellular proteins that promote signal transduction through cell-cell or cell-matrix interaction. The diversity of functionality between each protein is specific to the many aspects of healthy and cancer biology. For example, CCN family proteins modulate cell adhesion, proliferation, migration, invasiveness, apoptosis, and survival.

CCN5 activation by free or encapsulated EGCG is required to render triple-negative breast cancer cell viability and tumor progression.

Epigallocatechin-3-gallate (EGCG) has been considered an anticancer agent despite conflicting and discrepant bioavailability views. EGCG impairs the viability and self-renewal capacity of triple-negative breast cancer (TNBC) cells and makes them sensitive to estrogen via activating ER-α. Surprisingly, the mechanism of EGCG's action on TNBC cells remains unclear.

Downregulation of miR-506-3p Facilitates EGFR-TKI Resistance through Induction of Sonic Hedgehog Signaling in Non-Small-Cell Lung Cancer Cell Lines.

Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR-targeted tyrosine kinase inhibitors (TKIs). Treatment resistance remains the primary obstacle to the successful treatment of NSCLC. Although drug resistance mechanisms have been studied extensively in NSCLC, the regulation of these mechanisms has not been completely understood.

pH-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), a metabolic disorder, remains one of the leading cancer mortality sources worldwide. An initial response to treatments, such as gemcitabine (GEM), is often followed by emergent resistance reflecting an urgent need for alternate therapies. The PDAC resistance to GEM could be due to ERK1/2 activity.

Chemical Architecture of Block Copolymers Differentially Abrogate Cardiotoxicity and Maintain the Anticancer Efficacy of Doxorubicin.

The molecular architecture of pH-responsive amphiphilic block copolymers, their self-assembly behavior to form nanoparticles (NPs), and doxorubicin (DOX)-loading technique govern the extent of DOX-induced cardiotoxicity. We observed that the choice of pH-sensitive tertiary amines, surface charge, and DOX-loading techniques within the self-assembled NPs strongly influence the release and stimulation of DOX-induced cardiotoxicity in primary cardiomyocytes. However, covalent conjugation of DOX to a pH-sensitive nanocarrier through a "conditionally unstable amide" linkage (PCPY-cDOX; PC = polycarbonate and PY = 2-pyrrolidine-1-yl-ethyl-amine) significantly reduced the cardiotoxicity of DOX in cardiomyocytes as compared to noncovalently encapsulated DOX NPs (PCPY-eDOX).

Microenvironment-sensing, nanocarrier-mediated delivery of combination chemotherapy for pancreatic cancer.

Limited effectiveness of Raf and MEK inhibitors has impelled the interest to use the inhibitors of Extra-cellular Receptor Kinase (ERK) pathway in combination with Gemcitabine (GEM) in pancreatic cancer. However, off-target abundance of ERK receptors, challenging physico-chemical properties, and dose-limiting toxicity of the inhibitor has presented critical challenges towards fabricating this combination amenable for clinical translation. Herein we report a pharmaceutical nanoformulation of GEM and an ERK inhibitor (SCH 772984) co-stabilized within a pH-sensing nanocarrier (NC, with a hydrodynamic diameter of 161 ± 5.

A novel triazole, NMK-T-057, induces autophagic cell death in breast cancer cells by inhibiting γ-secretase-mediated activation of Notch signaling.

Notch signaling is reported to be deregulated in several malignancies, including breast, and the enzyme γ-secretase plays an important role in the activation and nuclear translocation of Notch intracellular domain (NICD). Hence, pharmacological inhibition of γ-secretase might lead to the subsequent inhibition of Notch signaling in cancer cells. In search of novel γ-secretase inhibitors (GSIs), we screened a series of triazole-based compounds for their potential to bind γ-secretase and observed that 3-(3'4',5'-trimethoxyphenyl)-5-(-methyl-3'-indolyl)-1,2,4-triazole compound (also known as NMK-T-057) can bind to γ-secretase complex.

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) develops extrinsic- and intrinsic-resistant phenotypes to prevent chemotherapies from entering into the cells by promoting desmoplastic reactions (DR) and metabolic malfunctions of the drugs. It is well established that these responses are also associated with pancreatic cancer cells' gemcitabine resistance. However, the mechanism by which these resistant pathways function in the pancreatic cancer cells remains poorly understood.

Aspirin suppresses tumor cell-induced angiogenesis and their incongruity.

Tumor neovascularization/tumor angiogenesis is a pathophysiological process in which new blood vessels are formed from existing blood vessels in the primary tumors to supply adequate oxygen and nutrition to cancer cells for their proliferation and metastatic growth to the distant organs. Therefore, controlling tumor angiogenesis is an attractive target for cancer therapy. Structural abnormalities of the vasculature (i.

Protein PEGylation for cancer therapy: bench to bedside.

PEGylation is a biochemical modification process of bioactive molecules with polyethylene glycol (PEG), which lends several desirable properties to proteins/peptides, antibodies, and vesicles considered to be used for therapy or genetic modification of cells. However, PEGylation of proteins is a complex process and can be carried out using more than one strategy that depends on the nature of the protein and the desired application. Proteins of interest are covalently conjugated or non-covalently complexed with inert PEG strings.

MIND model for triple-negative breast cancer in syngeneic mice for quick and sequential progression analysis of lung metastasis.

Mouse models of breast cancer with specific molecular subtypes (e.g., ER or HER2 positive) in an immunocompetent or an immunocompromised environment significantly contribute to our understanding of cancer biology, despite some limitations, and they give insight into targeted therapies.

The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF-ERK signaling.

Myc-associated zinc-finger protein (MAZ) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression is associated with the progression of pancreatic ductal adenocarcinoma (PDAC). However, the mechanism of action of MAZ in PDAC progression is largely unknown.

Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway.

Background: In menopausal women, one of the critical risk factors for breast cancer is obesity/adiposity. It is evident from various studies that leptin, a 16 kDa protein hormone overproduced in obese people, plays the critical role in neovascularization and tumorigenesis in breast and other organs. However, the mechanisms by which obesity influences the breast carcinogenesis remained unclear.

The Role of Compounds Derived from Natural Supplement as Anticancer Agents in Renal Cell Carcinoma: A Review.

Renal Cell Carcinoma (RCC) is the most prominent kidney cancer derived from renal tubules and accounts for roughly 85% of all malignant kidney cancer. Every year, over 60,000 new cases are registered, and about 14,000 people die from RCC. The incidence of this has been increasing significantly in the U.

Racial disparity in breast cancer: can it be mattered for prognosis and therapy.

Breast cancer (BC) has emerged as a deadly disease that affects the lives of millions of women worldwide. It is the second leading cause of cancer-related deaths in the United States. Advancements in BC screening, preventive measures and treatment have resulted in significant decline in BC related deaths.

Deficiency of CCN5/WISP-2-Driven Program in breast cancer Promotes Cancer Epithelial cells to mesenchymal stem cells and Breast Cancer growth.

Breast cancer progression and relapse is conceivably due to tumor initiating cells (TICs)/cancer stem cells. EMT (epithelial-mesenchymal-transition)-signaling regulates TICs' turnover. However, the mechanisms associated with this episode are unclear.

An exploration of the socio-economic profile of women and costs of receiving abortion services at public health facilities of Madhya Pradesh, India.

Background: Maternal mortality, which primarily burdens developing countries, reflects the greatest health divide between rich and poor. This is especially pronounced for access to safe abortion services which alone avert 1 of every 10 maternal deaths in India. Primarily due to confidentiality concerns, poor women in India prefer private services which are often offered by untrained providers and may be expensive.

Evaluating the relative effectiveness of high-intensity and low-intensity models of behaviour change communication interventions for abortion care-seeking in Bihar and Jharkhand, India: a cross-sectional study.

Background: This study aimed to compare the effectiveness of a high-intensity model (HIM) and a low-intensity model (LIM) of behaviour change communication interventions in Bihar and Jharkhand states of India designed to improve women's knowledge and usage of safe abortion services, as well as the dose effect of intervention exposure.

Methods: We conducted two cross-sectional household surveys among married women aged 15-49 years in intervention and comparison districts. Difference-in-difference models were used to assess the efficacy of the intervention, adjusting for sociodemographic characteristics.

Detection of CCN1 and CCN5 mRNA in Human Cancer Samples Using a Modified In Situ Hybridization Technique.

In situ hybridization is an ideal tool for the detection and localization of mRNA expression of specific gene(s) in tissue sections and cell lines for prognosis, predictive markers, and highlighted potential therapeutic targets. Given the importance of CCN1 and CCN5 in breast and pancreatic cancer progression, these two secretory proteins could be novel therapeutic targets. Thus, evaluating the distribution of mRNA of these targets using in situ hybridization could be important preclinical tools.

Human pancreatic cancer progression: an anarchy among CCN-siblings.

Decades of basic and translational studies have identified the mechanisms by which pancreatic cancer cells use molecular pathways to hijack the normal homeostasis of the pancreas, promoting pancreatic cancer initiation, progression, and metastasis, as well as drug resistance. These molecular pathways were explored to develop targeted therapies to prevent or cure this fatal disease. Regrettably, the studies found that majority of the molecular events that dictate carcinogenic growth in the pancreas are non-actionable (potential non-responder groups of targeted therapy).

Exosomes in carcinogenesis: molecular palkis carry signals for the regulation of cancer progression and metastasis.

Exosomes, which act as biological cargo vessels, are cell-released, phospholipid-enclosed vesicles. In eukaryotic cells, exosomes carry and exchange biological materials or signals for the benefit or detriment to the cells. Thereby, we consider exosomes to be molecular Palkis (carriers).