Researchers have discovered a DNA derivative that inhibits a key enzyme associated with the worsening of the excessive growth of cancer cells, showing promise as an antiproliferative cancer treatment.
Widely known for its role in maintaining bone mineral density, Vitamin D3 is also purported to be anticancerous as there has been a correlation between Vitamin D3 deficiency and worseninghealth outcomes in cancer patients. This is due to Vitamin D3’s inhibitory effects on an enzyme called CYP24A1 (known as CYP24 from here onwards), an overexpression of which has been linked to more aggressive cancer tumour growth. Thus, CYP24 inhibition has been explored as a potential therapeutic target to slow down the progression of cancer.
Many research attempts have been made todevelop molecules that limit or inhibit the activity of CYP24, including some that mimic the function of Vitamin D3. Disappointingly, many of the attempts did not exhibit sufficient clinical response or had too many undesirable side effects to be properly considered for cancer treatment.
Fortunately, Madhu Biyani from Kanazawa University and her team, in collaboration with teams from Toyama Prefectural University and BioSeeds Corporation, have discovered a DNA derivative that successfully inhibits CYP24 activity as well as the mechanism for which it acts on CYP24.
The researchers sorted through many DNA aptamers – short, single-stranded nucleic acid sequencesthat may selectively bind to targeted biomolecules like carbohydrates, peptides, and proteins. They were specifically interested in finding DNA aptamers that would bind to CYP24 but not CYP27B1, an enzyme that synthesises Vitamin D3.
A total of 11DNA aptamers were shortlisted for experimentation, where all of them were testedfor CYP24 inhibition activity in the lab setting. Only four candidates that inhibited only CYP24 but not CYP27B1 remained, and only one (Apt-7) was put under further scrutiny.
Biyani and team used computer software to generate simulations of the binding of Apt-7 to CYP24, in which a prediction of the fit of Apt-7 in the active site of the enzyme and the implications of this process were generated (also known as a molecular docking scenario). This prediction was then checked experimentally by adding Apt-7 to a mixture of CYP24 and vitamin D3, which confirmed their hypothesis.The researchers also verified the molecular docking scenario by subjecting both Apt-7 and CYP24to atomic force microscopy to discern their structures as the binding occurred, further confirming the inhibitory action of Apt-7 on CYP24.
To further probe the applications of their discovery, the team studied the effect of Apt-7 on cancer cells. The findings were promising, with Apt-7 showing strong inhibitory properties on CYP24 in the cancer cells, mitigating the effects of its overexpression and slowing down the proliferation of the cancer cells. With such promising findings,Biyani hopes that DNA aptamer-based molecules will become a promising lead for cancer therapies.
Source: Biyani et al. (2022). Novel DNA Aptamer for CYP24A1 Inhibition with Enhanced Antiproliferative Activity in Cancer Cells.ACS Applied Materials & Interfaces,14(16), 18064-18078.