Isoquinolinequinone N-oxides with diverging mechanisms of action induce collateral sensitivity against multidrug resistant cancer cells.

Multidrug resistance (MDR) is a major challenge in cancer research. Collateral sensitizers, compounds that exploit the enhanced defense mechanisms of MDR cells as weaknesses, are a proposed strategy to overcome MDR. Our previous work reported the synthesis of two novel Isoquinolinequinone (IQQ) N-oxides that induce collateral sensitivity in MDR ABCB1-overexpressing non-small cell lung cancer (NSCLC) and colorectal cancer cells.

Hypoxia as a critical player in extracellular vesicles-mediated intercellular communication between tumor cells and their surrounding microenvironment.

In the past years, increasing attention has been paid to the role of extracellular vesicles (EVs) as mediators of intercellular communication in cancer. These small size particles mediate the intercellular transfer of important bioactive molecules involved in malignant initiation and progression. Hypoxia, or low partial pressure of oxygen, is recognized as a remarkable feature of solid tumors and has been demonstrated to exert a profound impact on tumor prognosis and therapeutic efficacy.

Preclinical studies on the antitumor and non-toxic effect of combining pirfenidone with vinorelbine and carboplatin in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) shows limited therapeutic response to vinorelbine and carboplatin. Combining these drugs with an antifibrotic drug may enhance their antitumor effect. Pirfenidone is an antifibrotic drug whose antitumor activity has been described in different types of cancer.

Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC.

Discovery of Potent Isoquinolinequinone -Oxides to Overcome Cancer Multidrug Resistance.

Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ -oxide derivatives in two isomeric families, both exhibiting nanomolar GI against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI > 2 times lower than the corresponding C(7) isomers.

Chemosensitizing effect of pentoxifylline in sensitive and multidrug-resistant non-small cell lung cancer cells.

Multidrug resistance (MDR) is frequent in non-small cell lung cancer (NSCLC) patients, which can be due to its fibrotic stroma. This work explores the combination of pentoxifylline, an anti-fibrotic and chitinase 3-like-1 (CHI3L1) inhibitor drug, with conventional chemotherapy to improve NSCLC treatment. The effect of pentoxifylline in the expression levels of P-glycoprotein (P-gp), CHI3L1 and its main downstream proteins, as well as on cell death, cell cycle profile, and P-gp activity was studied in two pairs of sensitive and MDR counterpart NSCLC cell lines (NCI-H460/NCI-H460/R and A549/A549-CDR2).

Special Issue: "Drug Repurposing for Cancer Therapies".

Cancer is one of the primary global causes of death, thus addressing cancer therapy remains a significant challenge, especially in cases where cancers exhibit resistance to treatment [...

Novel family of [RuCp(N,N)(P)] compounds with simultaneous anticancer and antibacterial activity: Biological evaluation and solution chemistry studies.

A family of ten novel ruthenium(II)-cyclopentadienyl organometallics of general formula [Ru(η-CH)(N,N)(PPh(CHCOOR)][CFSO] (1-10) in which (N,N) = 4,4'-R'-2,2'-bipyridyl (R = -H or -CHCHOH; R' = -H, -CH, -OCH, -CHOH, and -CH-biotin) was prepared from [Ru(η-CH)(PPh(CHCOOH))Cl]. All compounds were fully characterized by means of several spectroscopic and analytical techniques, and the molecular structures of [Ru(η-CH)(PPh(CHCOOH))Cl], 1, 3 and 4 have been additionally studied by single-crystal X-ray diffraction. The anticancer activity of all compounds was evaluated in sensitive and multidrug-resistant counterpart cell lines from human colorectal cancer (Colo 205 and Colo 320) and non-small cell lung cancer NSCLC (A549, NCI-H460 versus NCI-H460/R) as well.

Evaluation of the Cytotoxic and Antiviral Effects of Small Molecules Selected by In Silico Studies as Inhibitors of SARS-CoV-2 Cell Entry.

The spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) relies on host cell surface glycans to facilitate interaction with the angiotensin-converting enzyme 2 (ACE-2) receptor. This interaction between ACE2 and the spike protein is a gateway for the virus to enter host cells and may be targeted by antiviral drugs to inhibit viral infection. Therefore, targeting the interaction between these two proteins is an interesting strategy to prevent SARS-CoV-2 infection.

The role of Extracellular Vesicles in glycolytic and lipid metabolic reprogramming of cancer cells: Consequences for drug resistance.

In order to adapt to a higher proliferative rate and an increased demand for energy sources, cancer cells rewire their metabolic pathways, a process currently recognized as a hallmark of cancer. Even though the metabolism of glucose is perhaps the most discussed metabolic shift in cancer, lipid metabolic alterations have been recently recognized as relevant players in the growth and proliferation of cancer cells. Importantly, some of these metabolic alterations are reported to induce a drug resistant phenotype in cancer cells.

Fibroblasts in pancreatic cancer: molecular and clinical perspectives.

Pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) are highly abundant cells in the pancreatic tumor microenvironment (TME) that modulate desmoplasia. The formation of a dense stroma leads to immunosuppression and therapy resistance that are major causes of treatment failure in pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that several subpopulations of CAFs in the TME can interconvert, explaining the dual roles (antitumorigenic and protumorigenic) of CAFs in PDAC and the contradictory results of CAF-targeted therapies in clinical trials.

Repurposing some of the Well-known Non-steroid Anti-inflammatory Drugs (NSAIDs) for Cancer Treatment.

Drug repurposing is a strategy used to develop new treatments based on approved or investigational drugs outside the scope of their original clinical indication. Since this approach benefits from the original toxicity data of the repurposed drugs, the drug-repurposing strategy is timesaving, and inexpensive. It has a higher success rate compared to traditional drug discovery.

Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells.

Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms.

The role of extracellular vesicles in the transfer of drug resistance competences to cancer cells.

Drug resistance remains a major hurdle to successful cancer treatment, being accountable for approximately 90% of cancer-related deaths. In the past years, increasing attention has been given to the role of extracellular vesicles (EVs) in the horizontal transfer of drug resistance in cancer. Indeed, many studies have described the dissemination of therapy resistance traits mediated by EVs, which may be transferred from drug resistant tumor cells to their drug sensitive counterparts.

Pirfenidone Sensitizes NCI-H460 Non-Small Cell Lung Cancer Cells to Paclitaxel and to a Combination of Paclitaxel with Carboplatin.

Pirfenidone, an antifibrotic drug, has antitumor potential against different types of cancers. Our work explored whether pirfenidone sensitizes non-small cell lung cancer (NSCLC) cell lines to chemotherapeutic treatments. The cytotoxic effect of paclitaxel in combination with pirfenidone against three NSCLC cell lines (A549, NCI-H322 and NCI-H460) was evaluated using the sulforhodamine B assay.

3D Cell Culture Models as Recapitulators of the Tumor Microenvironment for the Screening of Anti-Cancer Drugs.

Today, innovative three-dimensional (3D) cell culture models have been proposed as viable and biomimetic alternatives for initial drug screening, allowing the improvement of the efficiency of drug development. These models are gaining popularity, given their ability to reproduce key aspects of the tumor microenvironment, concerning the 3D tumor architecture as well as the interactions of tumor cells with the extracellular matrix and surrounding non-tumor cells. The development of accurate 3D models may become beneficial to decrease the use of laboratory animals in scientific research, in accordance with the European Union's regulation on the 3R rule (Replacement, Reduction, Refinement).

Impact of cancer metabolism on therapy resistance - Clinical implications.

Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options.

Different Ability of Multidrug-Resistant and -Sensitive Counterpart Cells to Release and Capture Extracellular Vesicles.

Cancer multidrug resistance (MDR) is one of the main challenges for cancer treatment efficacy. MDR is a phenomenon by which tumor cells become resistant to several unrelated drugs. Some studies have previously described the important role of extracellular vesicles (EVs) in the dissemination of a MDR phenotype.

Synthesis of Novel Methyl 3-(hetero)arylthieno[3,2-]pyridine-2-carboxylates and Antitumor Activity Evaluation: Studies In Vitro and In Ovo Grafts of Chick Chorioallantoic Membrane (CAM) with a Triple Negative Breast Cancer Cell Line.

A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-]pyridine-2-carboxylates - were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothieno[3,2-]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines-MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated.

Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%.

Development of potent CPP6-gemcitabine conjugates against human prostate cancer cell line (PC-3).

Gemcitabine (dFdC) is a nucleoside analogue used in the treatment of various cancers, being a standard treatment for advanced pancreatic cancer. The effect of gemcitabine is severely compromised due to its rapid plasma degradation, systemic toxicity and drug resistance, which restricts its therapeutic efficacy. Our main goal was to develop new active conjugates of dFdC with novel cell-penetrating hexapeptides (CPP6) to facilitate intracellular delivery of this drug.

Chitinase 3-like-1 and fibronectin in the cargo of extracellular vesicles shed by human macrophages influence pancreatic cancer cellular response to gemcitabine.

Tumour-associated macrophages have been implicated in pancreatic ductal adenocarcinoma (PDAC) therapy response and Extracellular vesicles (EVs) shed by macrophages might have a role in this process. Here, we demonstrated that large EVs released by anti-inflammatory human macrophages decreased PDAC cellular sensitivity to gemcitabine. Using proteomic analysis, chitinase 3-like-1 (CHI3L1) and fibronectin (FN1) were identified as two of the most abundant proteins in the cargo of macrophages-derived EVs.

The Role of Extracellular Vesicles in the Hallmarks of Cancer and Drug Resistance.

Extracellular vesicles (EVs) mediate intercellular signaling and communication, allowing the intercellular exchange of proteins, lipids, and genetic material. Their recognized role in the maintenance of the physiological balance and homeostasis seems to be severely disturbed throughout the carcinogenesis process. Indeed, the modus operandi of cancer implies the highjack of the EV signaling network to support tumor progression in many (if not all) human tumor malignancies.