Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors.

SMADs are the canonical intracellular effector proteins of the TGF-β (transforming growth factor-β). SMADs translocate from plasma membrane receptors to the nucleus regulated by many SMAD-interacting proteins through phosphorylation and other post-translational modifications that govern their nucleocytoplasmic shuttling and subsequent transcriptional activity. The signaling pathway of TGF-β/SMAD exhibits both tumor-suppressing and tumor-promoting phenotypes in epithelial-derived solid tumors.

Fibronectin, DHPS and SLC3A2 Signaling Cooperate to Control Tumor Spheroid Growth, Subcellular eIF5A1/2 Distribution and CDK4/6 Inhibitor Resistance.

Extracellular matrix (ECM) protein expression/deposition within and stiffening of the breast cancer microenvironment facilitates disease progression and correlates with poor patient survival. However, the mechanisms by which ECM components control tumorigenic behaviors and responses to therapeutic intervention remain poorly understood. Fibronectin (FN) is a major ECM protein controlling multiple processes.

Metadherin Regulates Inflammatory Breast Cancer Invasion and Metastasis.

Inflammatory breast cancer (IBC) is one of the most lethal subtypes of breast cancer (BC), accounting for approximately 1-5% of all cases of BC. Challenges in IBC include accurate and early diagnosis and the development of effective targeted therapies. Our previous studies identified the overexpression of metadherin (MTDH) in the plasma membrane of IBC cells, further confirmed in patient tissues.

enhances carboplatin chemotherapy effect by inhibiting the DNA damage response pathway and stemness.

Inflammatory Breast Cancer (IBC) is a rare and aggressive type of breast cancer with a poor prognosis. Its management is challenging because of a lack of targeted therapies, increased metastatic potential, and high recurrence rates. Interest in using platinum agents such as carboplatin emerged from data suggesting frequent DNA repair defects in breast cancer.

Accumulation of amyloid beta (Aβ) and amyloid precursor protein (APP) in tumors formed by a mouse xenograft model of inflammatory breast cancer.

Accumulation of amyloid in breast cancer is a well-known phenomenon, but only immunoglobulin light-chain amyloidosis (AL) or transthyretin (TTR) amyloid had been detected in human breast tumor samples previously. We recently reported that another amyloidogenic peptide, amyloid beta (Aβ), is present in an aggregated form in animal and human high-grade gliomas and suggested that it originates systemically from the blood, possibly generated by platelets. To study whether breast cancers are also associated with these Aβ peptides and in what form, we used a nude mouse model inoculated with triple-negative inflammatory breast cancer cell (SUM-149) xenografts, which develop noticeable tumors.

Extract Reduces the Motility of Breast Cancer Cells Mediated by the RAC⁻Lamellipodin Axis.

Breast cancer (BC) is the second leading cause of cancer death among women worldwide. The main cause of BC morbidity and mortality is the invasiveness capacity of cancer cells that may lead to metastasis. Here, we aimed to investigate the therapeutic efficacy of extract (GLE)-a medicinal mushroom with anticancer properties-on BC motility via the Rac/Lamellipodin pathway.

Identification of Biologically Active Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities .

We previously reported that extract (GLE) demonstrate significant anti-cancer activity against triple negative inflammatory breast cancer models. Herein, we aimed to elucidate the bioactive compounds of GLE responsible for this anti-cancer activity. We performed NMR, X-ray crystallography and analog derivatization as well as anti-cancer activity studies to elucidate and test the compounds.

extract (GLE) impairs breast cancer stem cells by targeting the STAT3 pathway.

The aggressive nature of triple negative breast cancer (TNBC) may be explained in part by the presence of breast cancer stem cells (BCSCs), a subpopulation of cells, which are involved in tumor initiation, progression, metastasis, recurrence, and therapy resistance. The signal transducer and activator of transcription 3 (STAT3) pathway participates in the development and progression of BCSCs, but its role in TNBC remains unclear. Here, we report that extract (GLE), a medicinal mushroom with anticancer activity, acts on BCSCs and in TNBC pre-clinical animal tumor models by downregulating the STAT3 pathway.

Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria.

The first total synthesis of a C5-curcumin-2-hexadecynoic acid (C5-Curc-2-HDA, 6) conjugate was successfully performed. Through a three-step synthetic route, conjugate 6 was obtained in 13% overall yield and tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Our results revealed that 6 was active against eight MRSA strains at MICs that range between 31.

The (5Z)-5-Pentacosenoic and 5-Pentacosynoic Acids Inhibit the HIV-1 Reverse Transcriptase.

The natural fatty acids (5Z)-5-pentacosenoic and (9Z)-9-pentacosenoic acids were synthesized for the first time in eight steps starting from either 4-bromo-1-butanol or 8-bromo-1-butanol and in 20-58% overall yields, while the novel fatty acids 5-pentacosynoic and 9-pentacosynoic acids were also synthesized in six steps and in 34-43% overall yields. The ∆(5) acids displayed the best IC50's (24-38 µM) against the HIV-1 reverse transcriptase (RT) enzyme, comparable to nervonic acid (IC50 = 12 µM). The ∆(9) acids were not as effective towards HIV-RT with the (9Z)-9-pentacosenoic acid displaying an IC50 = 54 µM and the 9-pentacosynoic acid not inhibiting the enzyme at all.

Synthesis of novel C5-curcuminoid-fatty acid conjugates and mechanistic investigation of their anticancer activity.

The first synthesis of C5-curcumin-fatty acid (C5-Curc-FA) conjugates was successfully performed. Through a two-step synthetic route, 10 analogs were synthesized for a structure-activity relationship (SAR) study. It was found that C5-Curc-FA conjugates containing either decanoic acid or palmitic acid moieties were cytotoxic against colorectal adenocarcinoma cell (CCL-229) at IC50s ranging from 22.