Journal Article

Uncovering Cell Cycle Dysregulations and Associated Mechanisms in Cancer and Neurodegenerative Disorders: A Glimpse of Hope for Repurposed Drugs

Kumar, Pravir, Advani, Dia

2024

Overview

The cell cycle is the sequence of events orchestrated by a complex network of cell cycle proteins. Unlike normal cells, mature neurons subsist in a quiescent state of the cell cycle, and aberrant cell cycle activation triggers neuronal death accompanied by neurodegeneration. The periodicity of cell cycle events is choreographed by various mechanisms, including DNA damage repair, oxidative stress, neurotrophin activity, and ubiquitin-mediated degradation. Given the relevance of cell cycle processes in cancer and neurodegeneration, this review delineates the overlapping cell cycle events, signaling pathways, and mechanisms associated with cell cycle aberrations in cancer and the major neurodegenerative disorders. We suggest that dysregulation of some common fundamental signaling processes triggers anomalous cell cycle activation in cancer cells and neurons. We discussed the possible use of cell cycle inhibitors for neurodegenerative disorders and described the associated challenges. We propose that a greater understanding of the common mechanisms driving cell cycle aberrations in cancer and neurodegenerative disorders will open a new avenue for the development of repurposed drugs. Graphical Abstract Cell cycle activation and cell cycle re-entry are the two critical cellular phenomena associated with cancer and neurodegeneration, respectively. Various regulatory proteins, such as cyclin-dependent kinases (CDKs), cyclins, and checkpoint kinases, control the cell cycle dynamics at different phases. Further, the integrity of cell cycle is controlled by different mechanisms like DNA damage response, oxidative stress, neurotrophin activity, and the ubiquitin–proteasome system (UPS), the alterations which play an essential role in the pathogenesis of both cancer and neurodegenerative disorders. Pharmacological targeting of important cell cycle regulatory molecules like the application of CDK inhibitors, PARP inhibitors, checkpoint kinase inhibitors, and microtubule inhibitors holds great promise for treating various human cancers and can be repurposed for different neurodegenerative disorders.

• Publisher: Springer US,Springer Nature B.V
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Cancer / Cell activation / Cell Biology / Cell cycle / Cell Cycle - drug effects / Cell death / Cyclin-dependent kinases / Cyclins / DNA damage / DNA repair / Drug development / Drug Repositioning / Humans / Kinases / Neoplasms - drug therapy / Neoplasms - metabolism / Neoplasms - pathology / Neurobiology / Neurodegeneration / Neurodegenerative diseases / Neurodegenerative Diseases - drug therapy / Neurodegenerative Diseases - metabolism / Neurology / Neurosciences / Nucleotide sequence / Oxidative stress / Periodicity / Proteasomes / Regulatory proteins / Review / Signal Transduction - drug effects / Ubiquitin