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Can anti-cancer drugs be used as an effective therapy for the treatment of Alzheimer’s disease?

Alzheimer’s disease (AD) is a complex irreversible multifactorial disorder. Excessive hyperphosphorylation of tau seems to be essential in the pathophysiology of AD, as hyperphosphorylated tau aggregates into neurofibrillary tangles (NFT) that cause the disease. Several studies have established that hyperphosphorylation of tau might be due to increased levels of tau kinase (s) such as epidermal growth factor receptor tyrosine kinase (EGFR-RTK). Few recent animal studies have demonstrated the valuable effects of EGFR inhibitors in different experimental models of AD. Unlike many previously tested EGFR inhibitors that have poor blood-brain barrier permeability, we have found that lapatinib ditosylate, an EGFR inhibitor with good BBB permeability approved as anticancer, ameliorated AD-like pathological changes in an experimental rodent AD model.

Background

Worldwide, around 50 million people have dementia. According to the World Health Organization reports, this number is expected to increase threefold by 2050. Alzheimer’s disease (AD) is the most common type of dementia, which is characterised by deterioration in cognition and behaviour. The underlying aetiopathogenesis of AD is still little understood. The amyloid plaques theory and tau hyperphosphorylation are two of the most prominent theories of AD. Tau stabilises structures critical to the internal transport system called microtubules. The tau theory states that excessive phosphorylation of tau leads to the formation of NFTs. The phosphorylation state of tau is controlled by an equilibrium between phosphatase(s) activity, and kinase(s) activity. Therefore, suppression of such kinases would be an up-and-coming strategy to inhibit tau hyperphosphorylation (Tavassoly et al,2020).

Neuroprotective effects of different EGFR inhibitors in Alzheimer’s disease

Over the last decade, few studies have reported the potential therapeutic effects of anti-cancer epidermal growth factor receptors (EGFR) inhibitors, on the improvement of neurological and behavioural symptoms in neurodegenerative disorders such as Parkinson’s disease, and AD. The inverse relationship between cancer and AD has prompted a clinical trial in AD using masitinib, as an approved anti-cancer drug, which reversed cognitive deterioration in mild AD patients. Multiple reports have demonstrated the neuroprotective effects of many EGFR inhibitors such as erlotinib, gefitinib, afatinib, and CL-387, 785  in different AD models via numerous mechanisms such as activation of autophagy, amendment of Aβ plaques, and p-tau, inhibition of reactive astrocytes, and axonal regeneration via inhibition of glycogen synthase kinase-3β (GSK-3β) (Wang et al., 2012, 2017; Chen et al., 2019; Wakatsuki, 2019). Nonetheless, there are several limitations to test EGFR inhibitors in prospective clinical trials. For example, drugs such as gefitinib and erlotinib were designed for peripheral types of tumours and display weak effects in metastatic brain tumours because they do not reveal optimum BBB permeability.

In recent work (Mansour et al., 2021), we demonstrate that oral administration of lapatinib ditosylate (LAP), a BBB permeable dual EGFR-TKI, in Alzheimer’s rat model for 3 weeks improved memory and ameliorated histopathological changes. LAP reversed AD pathological hallmarks; Aβ1-42, and p-tau, inhibited astrocyte reactivity via inhibition of glial acidic fibrillary protein (GFAP), suppressed excitotoxicity via inhibition of glutamate receptors-II. Furthermore, LAP curbed neuroinflammation via suppression of P38-MAPK and TNF-α, exerted anti-oxidant effect via reduction of NADPH oxidase-1 expression, promoted autophagy via inhibition of p-mTOR, along with activation of the prosurvival pathway; PI3K/Akt/GSK-3β. Our results offered a significant opportunity to spread awareness of the repositioning of BBB-permeable TKI anti-cancer drugs for the treatment of AD (Mansour et al., 2021).

Future directions

Targeting EGFR might be a novel avenue in the treatment of AD. There are many FDA-approved EGFR inhibitors that can be repositioned for AD. Regardless of the optimistic neuroprotective effects of EGFR inhibitors in AD, there are only two recently published papers that used BBB-permeable inhibitors; lapatinib, and ibrutinib (Lee et al., 2021; Mansour et al., 2021). This scarcity of reports caused an obstacle in the possible repositioning of EGFR inhibitors in AD. Accordingly, several studies have to be conducted using the third generation of EGFR inhibitors, which are characterized by good CNS-penetrating capacities,  such as AZD3759 and dacomitinib. Surprisingly, the machine learning framework has recommended lapatinib as a possible candidate for repositing for AD (Rodriguez et al., 2021). We think that the machine learning technique will help to address the question of whether anti-cancer drugs can be used as an effective therapy for the treatment of Alzheimer’s disease.

References

References Chen, Y.-J. et al. (2019) ‘Anti-inflammatory effect of afatinib (an EGFR-TKI) on OGD-induced neuroinflammation’, Scientific Reports. Nature Publishing Group, 9(1), p. 2516. Available at: https://doi.org/10.1038/s41598-019-38676-7.


Lee, H. et al. (2021) ‘Ibrutinib modulates Aβ/tau pathology, neuroinflammation, and cognitive function in mouse models of Alzheimer’s disease, Aging Cell. Blackwell Publishing Ltd, 20(3), p. e13332. Available at: https://doi.org/10.1111/acel.13332.


Mansour, H. M. et al. (2021) ‘Lapatinib ditosylate rescues memory impairment in D-galactose/ovariectomized rats: Potential repositioning of an anti-cancer drug for the treatment of Alzheimer’s disease.’, Experimental neurology. Academic Press, p. 113697. Available at: https://doi.org/10.1016/j.expneurol.2021.113697


Rodriguez, S. et al. (2021) ‘Machine learning identifies candidates for drug repurposing in Alzheimer’s disease, Nature Communications, 12(1). DOI: 10.1038/s41467-021-21330-0.


Tavassoly, O., Sato, T. and Tavassoly, I. (2020) ‘Inhibition of Brain EGFR Activation: A Novel Target in Neurodegenerative Diseases and Brain Injuries’, Molecular Pharmacology. American Society for Pharmacology & Experimental Therapeutics (ASPET), p. mol.120.119909. Available at:
https://doi.org/10.1124/mol.120.119909.


Wakatsuki, S. (2019) ‘Regulation of neuronal/axonal degeneration by ZNRF1 ubiquitin ligase’, Neuroscience Research. Elsevier, 139, pp. 21–25. Available at: https://doi.org/10.1016/j.neures.2018.07.008.


Wang, B. J. et al. (2017) ‘ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease’, Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 114(15), pp. E3129–E3138. Available at: https://doi.org/10.1073/pnas.1618804114


Wang, L. et al. (2012) ‘Epidermal growth factor receptor is a preferred target for treating Amyloid-β-induced memory loss’, Proceedings of the National Academy of Sciences of the United States of America, 109(41), pp. 16743–16748. Available at: https://doi.org/10.1073/pnas.1208011109.  

Written By

Heba M. Mansour1, Aiman S. El-Khatib2, and Mahmoud M. Khattab2
1 Department of Pharmacology, Egyptian Drug Authority, EDA, formerly NODCAR, Giza, Egypt. 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt.

Contact Details

Email: Heba_mansour77@yahoo.com
Telephone:
+01151090641

Address:
Egyptian Drug Authority,
51 Wezaret El-Zeraa st., Agouza, Giza, Egypt.
Egypt
OTHER
Egypt
111

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