Current Cancer Drug Targets - Volume 22, Issue 3, 2022

In vivo, tyrosine phosphorylation is a reversible and dynamic process governed by the opposing activities of protein tyrosine kinases and phosphatases. Defective or inappropriate operation of these proteins leads to aberrant tyrosine phosphorylation, which contributes to the development of many human diseases, including cancers. PTP1B, a non-transmembrane phosphatase, is generally considered a negative regulator of the metabolic signaling pathways and a promising drug target for type II diabetes and obesity. Recently, PTP1B is gaining considerable interest due to its important function and therapeutic potential in other diseases. An increasing number of studies have indicated that PTP1B plays a vital role in the initiation and progression of cancers and could be a target for new cancer therapies. Following recent advances in the aspects mentioned above, this review is focused on the major functions of PTP1B in different types of cancer and the underlying mechanisms behind these functions, as well as the potential pharmacological effects of PTP1B inhibitors in cancer therapy.

Human colorectal cancer (CRC) patient-derived organoids (PDOs) are a powerful ex vivo platform to directly assess the impact of molecular alterations and therapies on tumor cell proliferation, differentiation, response to chemotherapy, tumor-microenvironment interactions, and other facets of CRC biology. Next-generation sequencing studies have demonstrated that CRC is a highly heterogeneous disease with multiple distinct subtypes. PDOs are a promising new tool to study CRC due to their ability to accurately recapitulate their source tumor and thus reproduce this heterogeneity. This review summarizes the state-of-the-art for CRC PDOs in the study of cancer stem cells (CSCs) and the cancer stem cell niche. Areas of focus include the relevance of PDOs to understanding CSC-related paracrine signaling, identifying interactions between CSCs and the tumor microenvironment, and modeling CSC-driven resistance to chemotherapies and targeted therapies. Finally, we summarize current findings regarding the identification and verification of CSC targets using PDOs and their potential use in personalized medicine.

The p38 MAP kinases are a sub-family of the broad group of mitogen-activated serinethreonine protein kinases. The best-characterised, most widely expressed, and most targeted by drugs is p38α MAP kinase. This review briefly summarises the place of p38α MAP kinase in cellular signalling and discusses the structures and activity profiles of representative examples of the major classes of inhibitors and activators (both synthetic compounds and natural products) of this enzyme. Primary screening was direct in vitro inhibition of isolated p38α enzyme.

Cancer is a leading cause of death worldwide. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signalling pathway are activated abnormally, which promotes carcinogenesis. Several cytokines are important cancer drivers. These proteins bind to receptors and use the Janus kinase (JAK) and STAT pathways to communicate their responses. Cancer risks are linked to genetic differences in the JAK-STAT system. JAK inhibitors have been shown to reduce STAT initiation, tissue propagation, and cell existence in preclinical investigations involving solid tumour cell line models. JAK inhibitors, notably ruxolitinib, JAK1 or 2 blockers, make cell lines and mouse models more susceptible to radiotherapy, biological response modifier therapy, and oncolytic viral treatment. Numerous JAK antagonists have been or are now being evaluated in cancerous patients as monotherapy or by combining with other drugs in clinical studies. In preclinical investigations, certain JAK inhibitors showed promising anticancer effects; however, clinical trials explicitly evaluating their effectiveness against the JAK/STAT system in solid tumours have yet to be completed. JAK inhibition is a promising strategy to target the JAK/STAT system in solid tumours, and it deserves to be tested further in clinical studies. The function of directing Janus kinases (JAKs), an upstream accelerator of STATs, as a technique for lowering STAT activity in various malignant circumstances is summarized in this article, which will help scientists to generate more specific drug molecules in the future.

Ferroptosis is an iron-dependent nonapoptotic kind of regulated cell death resulting from the destruction of redox balance in the cytosol. Unlike apoptosis, ferroptosis is caused by an increase in intracellular iron and lipid peroxides that causes significant damage to the membrane lipid bilayer and mitochondria leading to cell death. Increased iron level in the cell promotes ROS production. Ferroptosis inducer molecules increase ROS production and inhibit the antioxidant defence mechanism to facilitate ferroptosis in cancer cells. Inhibition of GPX4, redox-active iron availability, and lipid peroxidation are major contributors to ferroptosis. Ferroptosis is involved in many diseases like heart disease, neurodegenerative disease, and cancer. Ferroptosis induction recently emerged as an attractive strategy for cancer therapy. In this review, we discuss the regulatory mechanism of ferroptosis, its different hallmarks, including genetic and metabolic regulators and inducers that promote ferroptosis in the cancer cells. Finally, the latest progress and development in ferroptosis research in different cancers focusing on proposing a novel strategy in cancer therapy are discussed.

Background: Triple-negative breast cancer (TNBC) is known for Warburg effect and defects in the mitochondria. AMP-dependent kinase (AMPK) activates the downstream transcription factors PGC-1α, PGC-1β, or FOXO1, which participate in mitochondrial biogenesis. 5- aminoimidazole-4-carboxamide riboside (AICAR) is an analog of adenosine monophosphate and is a direct activator of AMPK. Objectives: In the present study, we have made an attempt to understand the influence of AICAR on TNBC cells, MDA-MB-231, and the underlying changes in mitochondrial biogenesis, if any. Methods: We investigated AICAR induced changes in cell viability, apoptosis, migratory potential, and changes in the sensitivity of doxorubicin. Results: In response to the treatment of MDA-MB-231 breast cancer cells with 750 μM of AICAR for 72 hours, followed by 48 hours in fresh media without AICAR, we observed a decrease in viability via MTT assay, reduction in cell numbers along with the apoptotic appearance, increased cell death by ELISA, decreased lactate in conditioned medium and decrease in migration by scratch and transwell migration assays. These changes in the cancer phenotype were accompanied by an increase in mitochondrial biogenesis, as observed by increased mitochondrial DNA to nuclear DNA ratio, a decrease in lactic acid concentration, an increase in MitoTracker green and red staining, and increased expression of transcription factors PGC-1α, NRF-1, NRF-2, and TFAM, contributing to mitochondrial biogenesis. Pre-treatment of cells with AICAR for 72 hours followed by 48 hours treatment with 1 μM doxorubicin showed an increased sensitivity to doxorubicin as assessed by the MTT assay. Conclusion: Our results show that AICAR exerts beneficial effects on TNBC cells, possibly via switching off the Warburg effect and switching on the anti-Warburg effect through mitochondrial modulation.

Background: Increased CCKBR expression density or frequency has been reported in many neoplasms. Objective: We aimed to investigate whether CCKBR drives the growth of gastric cancer (GC) and its potential as a therapeutic target of immunotoxins. Methods: A lentiviral interference system was used to generate CCKBR-knockdown gastric cancer cells. Cell Counting Kit-8 and clonogenic assays were used to evaluate cell proliferation. Woundhealing and cell invasion assays were performed to evaluate cell mobility. Cell cycle was analyzed by flow cytometry. Tumor growth in vivo was investigated using a heterologous tumor transplantation model in nude mice. In addition, we generated the immunotoxin FQ17P and evaluated the combining capacity and tumor cytotoxicity of FQ17P in vitro. Results: Stable downregulation of CCKBR expression resulted in reduced proliferation, migration and invasion of BGC-823 and SGC-7901 cells. The impact of CCKBR on gastric cancer cells was further verified through CCKBR overexpression studies. Downregulation of CCKBR expression also inhibited the growth of gastric tumors in vivo. Furthermore, FQ17P killed CCKBR-overexpressing GC cells by specifically binding to CCKBR on the tumor cell surface. Conclusion: The CCKBR protein drives the growth, migration, and invasion of gastric cancer cells, and it might be a promising target for immunotoxin therapy based on its aberrant expression, functional binding interactions with gastrin, and subsequent internalization.