Drugging the cancer stem cell compartment: lessons learned from the hedgehog and Wnt signal transduction pathways.
ABSTRACT Cell-cell communication mediated by the secreted Hedgehog (Hh) and Wnt signaling molecules is essential to the coordination of cell fate decision making throughout the metazoan lifespan. From decades of genetically based interrogation, core components constituting the Hh and Wnt signal transduction pathways have been assembled, and a deep appreciation of how these signals elaborate distinct bodily tissues during development has been established. On the other hand, our incapacity to leverage similar genetic approaches to study adult organ systems has limited our understanding of how these molecules promote tissue renewal and regeneration through stem cell regulation. We discuss recent progress in the use of chemically based approaches to achieve control of these pathway activities in a broad range of biological studies and therapeutic contexts. In particular, we discuss the unique experimental opportunities that chemical modulators of these pathways afford in exploring the cancer stem cell hypothesis.
- SourceAvailable from: Hammad Mirza Mubeen[Show abstract] [Hide abstract]
ABSTRACT: Wnt-4 (wingless mouse mammary tumor virus integration site-4) protein is involved in many crucial embryonic pathways regulating essential processes. Aberrant Wnt-4 activity causes various anomalies leading to gastric, colon, or breast cancer. Wnt-4 is a conserved protein in structure and sequence. All Wnt proteins contain an unusual fold comprising of a thumb (or N-terminal domain) and index finger (or C-terminal domain) bifurcated by a palm domain. The aim of this study was to identify the best inhibitors of Wnt-4 that not only interact with Wnt-4 protein but also with the covalently bound acyl group to inhibit aberrant Wnt-4 activity. A systematic computational approach was used to analyze inhibition of Wnt-4. Palmitoleic acid was docked into Wnt-4 protein, followed by ligand-based virtual screening of nearly 209,847 compounds; conformer generation of 271 compounds resulted from extensive virtual screening and comparative docking of 10,531 conformers of 271 unique compounds through GOLD (Genetic Optimization for Ligand Docking), AutoDock-Vina, and FRED (Fast Rigid Exhaustive Docking) was subsequently performed. Linux scripts was used to handle the libraries of compounds. The best compounds were selected on the basis of having maximum interactions to protein with bound palmitoleic acid. These represented lead inhibitors in further experiments. Palmitoleic acid is important for efficient Wnt activity, but aberrant Wnt-4 expression can be inhibited by designing inhibitors interacting with both protein and palmitoleic acid.Drug Design, Development and Therapy 01/2015; 9:2449-61. DOI:10.2147/DDDT.S79784 · 3.03 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Evidence has accumulated that characterizes highly tumorigenic cancer cells residing in heterogeneous populations. The accepted term for such a subpopulation is cancer stem cells (CSCs). While many questions still remain about their precise role in the origin, progression, and drug resistance of tumors, it is clear they exist. In this review, a current understanding of the nature of CSC, their potential usefulness in prognosis, and the need to target them will be discussed. In particular, separate studies now suggest that the CSC is plastic in its phenotype, toggling between tumorigenic and nontumorigenic states depending on both intrinsic and extrinsic conditions. Because of this, a static view of gene and protein levels defined by correlations may not be sufficient to either predict disease progression or aid in the discovery and development of drugs to molecular targets leading to cures. Quantitative dynamic modeling, a bottom up systems biology approach whereby signal transduction pathways are described by differential equations, may offer a novel means to overcome the challenges of oncology today. In conclusion, the complexity of CSCs can be captured in mathematical models that may be useful for selecting molecular targets, defining drug action, and predicting sensitivity or resistance pathways for improved patient outcomes.Anti-cancer drugs 01/2014; 25(4). DOI:10.1097/CAD.0000000000000075 · 1.89 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Cancer stem cells (CSCs) have been identified in a growing list of malignancies and are believed to be responsible for cancer initiation, metastasis and relapse following certain therapies, even though they may only represent a small fraction of the cells in a given cancer. Like somatic stem cells and embryonic stem cells, CSCs are capable of self-renewal and differentiation into more mature, less tumorigenic cells that make up the bulk populations of cancer cells. Elimination of CSCs promises intriguing therapeutic potential and this concept has been adopted in preclinical drug discovery programs. Herein we will discuss the progress of these efforts, general considerations in practice, major challenges and possible solutions.Future medicinal chemistry 09/2014; 6(14):1567-85. DOI:10.4155/fmc.14.106 · 4.00 Impact Factor