Emerging Therapeutic Role of CDK Inhibitors in Targeting Cancer Stem Cells

Within a tumor, Cancer Stem Cells (CSCs) exists and own similar characteristics of a normal stem cell thus contributing towards aggressiveness of cancer by playing crucial role in tumor recurrence and metastasis capability. Various studies have been conducted to therapeutically target CSCs. One of the approaches include is to inhibit cell cycle progression in CSCs. Within last two decades cell cycle and role of various components in its regulation is firmly established. Cell cycle is regulated by Cyclin Dependent Kinases (CDK) bound to cyclin. CDK activity can be blocked by Cyclin-Dependent Kinase Inhibitors (CKIs) which can either bind cyclin/CDK complex or CDK alone and thus stops cell cycle. In this review various studies are discussed that have investigated the therapeutic role of CKIs in eradicating CSCs by inhibiting cell cycle. Overall, the analysis suggests that CKIs could be a potential therapeutic option in controlling CSCs populating in a tumor.

Targeting protein kinase CK2 in the treatment of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a disease with a very poor prognosis and limited treatment options. Although targeted therapies directed towards specific mutations found in CCA are becoming available and are showing great potential, many tumors do not carry actionable mutations and, in those that do, the emergence of drug resistance is a likely consequence of treatment. Therapeutic targeting of enzymes and other proteins that show elevated activity in CCA cells but which are not altered by mutation is a potential strategy for the treatment of target negative and drug-resistant disease. Protein kinase CK2 (CK2) is a ubiquitously expressed kinase that has increased expression and increased activity in a variety of cancer types including CCA. Several potent CK2 inhibitors are in pre-clinical development or under assessment in a variety of clinical trials often in combination with drugs that induce DNA damage. This review outlines the importance of CK2 in CCA and assesses the progress that has been made in the evaluation of CK2 inhibition as a treatment strategy in this disease. Targeting CK2 based on the expression levels or activity of this protein and/or in combination with drugs that induce DNA damage or inhibit cell cycle progression, could be a viable option for tumors that lack actionable mutations, or for tumors that develop resistance to targeted treatments.

M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

Glioblastoma multiforme (GBM) is the most malignant brain tumor. Hypoxic condition is a predominant feature of the GBM contributing to tumor growth and resistance to conventional therapies. Hence, the identification of drugs able to impair GBM malignancy and aggressiveness is considered of great clinical relevance. Previously, we demonstrated that the activation of M2 muscarinic receptors, through the agonist arecaidine propargyl ester (Ape), arrests cell proliferation in GBM cancer stem cells (GSCs). In the present work, we have characterized the response of GSCs to hypoxic condition showing an upregulation of hypoxia-inducible factors and factors involved in the regulation of GSCs survival and proliferation. Ape treatment in hypoxic conditions is however able to inhibit cell cycle progression, causing a significant increase of aberrant mitosis with consequent decreased cell survival. Additionally, qRT-PCR analysis suggest that Ape downregulates the expression of stemness markers and miR-210 levels, one of the main regulators of the responses to hypoxic condition in different tumor types. Our data demonstrate that Ape impairs the GSCs proliferation and survival also in hypoxic condition, negatively modulating the adaptive response of GSCs to hypoxia.

Antioestrogen-mediated cell cycle arrest and apoptosis induction in breast cancer and multiple myeloma cells

Antioestrogens (AEs) are synthetic molecules that block proliferation and induce apoptosis in breast cancer (BC) cells, principally by competing with oestradiol for binding to oestrogen receptors. Their antiproliferative activity and their pro-apoptotic capacity are well documented and a small number of molecules of this class are currently used clinically for the treatment of BC. AEs also inhibit cell cycle progression and/or induce apoptosis in multiple myeloma (MM) cells. Encouraging preliminary results have been obtained with patients and on xenografts with MM, providing a rational basis for the clinical use of AEs. This review focuses on antioestrogen-mediated signalling for blocking targets involved in the cell cycle, survival and apoptosis in both BC and MM cells. Improvement in our understanding of the mechanisms underlying the relationships between these compounds and their targets should lead to more beneficial therapeutic strategies.

Function and regulation of RhoE

The three Rnd proteins, Rnd1, Rnd2 and RhoE/Rnd3, are a subset of Rho family proteins that are unusual in that they bind but do not hydrolyse GTP, and are therefore not regulated by the classical GTP/GDP conformational switch of small GTPases. Increased expression of each Rnd protein induces loss of stress fibres in cultured fibroblasts and epithelial cells, acting antagonistically to RhoA, which stimulates stress fibre formation. RhoE is farnesylated and localizes partly on membranes, including the Golgi and plasma membrane, and in the cytosol. RhoE inhibits RhoA signalling in part by binding to the RhoA-activated serine/threonine kinase ROCK I (Rho-associated kinase I), thereby preventing it from phosphorylating its targets. RhoE activity is itself regulated by phosphorylation by ROCK I on multiple sites. RhoE phosphorylation enhances its stability, leading to an increase in RhoE levels. In addition, phosphorylation reduces its association with membranes and correlates with its ability to induce loss of stress fibres. RhoE also acts independently of ROCK to inhibit cell cycle progression, in part by preventing translation of cyclin D1, and to inhibit transformation of fibroblasts by oncogenic H-Ras. RhoE is therefore a multifunctional protein whose localization and actions are regulated by phosphorylation.