Flavopiridol: an antitumor drug with potential application in the treatment of neurodegenerative diseases

A novel synthetic compound PHID (8-Phenyl-6a, 7, 8, 9, 9a, 10-hexahydro-6H-isoindolo [5, 6-g] quinoxaline-7, 9-dione) protects SH-SY5Y cells against MPP+-induced cytotoxicity through inhibition of reactive oxygen species generation and JNK signaling

“…It is interesting to note that several compounds like flavopiridol, 17-(Allylamino)-17-demethoxygeldanamycin, and protocatechuic acid having profound antitumor activities also possess marked neuroprotective function (Pallas et al, 2005;Waza et al, 2006;Tseng et al, 1996). In search for developing novel therapeutic agents for treating neurodegenerative diseases including Parkinson's disease, we systematically screened isoindoloquinoxaline.…”

Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons

“…Furthermore, there has been report of the cell-cycle CDKs substrate pRb in postmortem PD brain samples, suggesting that cdk2, might be activated in this disease . Therefore, aberrant activation of cell cycle progression is a promising hypothesis underlying neuronal apoptosis, and may constitute a potential pharmacological target (Pallàs et al, 2005). So, it is possible to suggest that reentry into the cell cycle might be a common component of the process of neuronal cell death.…”

“…The neuroprotective effects of FLAV may be explained by the inhibition of CDKs implicated in cell cycle proliferation, thus preventing increased expression of E2F-1 (Phillips and Vousden, 2001). Other mechanisms involved in the neuroprotective properties of FLAV may be the inhibition of CDK5 and GSK-3␤ activity (Pallàs et al, 2005). Although this drug may have some undesirable side effects due to its antitumoral activity, according to the "two-hit hypothesis" the potential combination of an antioxidant (vit E) drug and a cell cycle inhibitor (FLAV) could be a potential treatment in the prevention of neurodegenerative processes.…”

Neuroprotective effects of caffeine against complex I inhibition–induced apoptosis are mediated by inhibition of the Atm/p53/E2F‐1 path in cerebellar granule neurons

“…It seems that ATM is activated as a transducer pathway, which in turn by phosphorylation activates a large number of proteins that convey the message activating several intracellular processes (McKinnon, 2001; McMurray, 2005; Ljungman, 2005). In addition to ATM, activation of cell‐cycle proteins, specifically the transcription factor E2F‐1, is also key in the neuronal apoptotic route (Hou et al, 2000, 2001; Phillips and Vousden, 2001; Smith et al, 2003; Verdaguer et al, 2004; Pallàs et al, 2005) consistent with reports suggesting that the expression of cell‐cycle proteins could constitute a convergent point in all neurodegenerative diseases (Becker and Bonni, 2004; Langley and Ratan, 2004). In support of this concept, we demonstrated for the first time that caffeine inhibits the expression of two key proapoptotic factors, E2F‐1 and p53.…”

“…A common characteristic of the brains of patients with neurodegenerative diseases like Alzheimer's and Parkinson's diseases is expression of cell‐cycle proteins (Zhu et al, 2000, 2004; Raina et al, 2001, 2004; Copani et al, 2001; Arendt, 2002; Bowser and Smith, 2002; Cash et al, 2002; Smith et al, 2003, 2004; Casadesus et al, 2005; Pallàs et al, 2005; Neve et al, 2006). Because neurons do not proliferate as they are postmitotic cells, several hypotheses have been proposed to explain the abnormal expression of these proteins.…”