New Potential for Anticancer Drugs

investigating cytochrome P450 inhibitors

a doctor and patients' hands

Did you know that your body detoxifies all sorts of compounds, sometimes to your detriment? In fact, those with experience in cancer research may have heard of a family of enzymes known as the cytochrome P450 (CYP) superfamily. This family of over 60 enzymes plays a key role in normal body function, mostly in the metabolism and excretion of toxins and drugs 1.

Potential Problems

The P450 family normally metabolize a large majority of xenobiotic compounds and render them harmless 1. However, their functions can go awry and end up activating some non-harmful compounds by converting them into carcinogenic byproducts, such as the case with polycyclic aromatic hydrocarbons 1.

Even more problematic, P450 proteins can become overexpressed in tumors, leading to tumor resistance to many anticancer drugs and chemotherapies 1. As can be expected, this constitutes a major hurdle in cancer research, as tumor resistance to a mainstream chemotherapy drug can cause significant complications for patients.

A recent paper published by Horley et al. used state-of-the-art research techniques to develop a solution to these problems. This paper outlies the synthesis and efficacy of a couple potent cytochrome P450 inhibitors which could be used therapeutically for drug resistant tumors (among other diseases).

Horley et al. began their study by investigating a known CYP1 inhibitor, the flavonoid alpha-naphthoflavone. The researchers discovered that chalcones, a biological precursor to flavones, share similar structure to the binding region of flavones and may serve as a suitable alternative as an inhibitory substance. Once they had synthesized their potential inhibitors, the scientists needed a method of testing these new compounds with active cytochrome P450 enzymes. To do this, they isolated the genes for a couple cytochromes from human liver and expressed them in baker’s yeast.

Horley et al. were able to demonstrate that their compounds could adequately inhibit human cytochrome P450 expressed in yeast cells. However, the question remained as to whether this action would translate to live human cells. To test this, the researchers used the ZymoPURE plasmid maxiprep system to isolate endotoxin-free plasmid that overexpresses a cytochrome P450 enzyme. This purified plasmid was transfected into HEK293 cells to evaluate the effects of the inhibitor on live human cells overexpressing the enzyme.

Resounding Success

The experiment was a resounding success - Horley et al. were able to demonstrate the potent inhibitory power of their compounds and introduce an additional avenue of investigation into the anticancer properties of cytochrome P450 enzyme inhibitors. This research wouldn’t be possible without the powerful experimental assays provided to by molecular cloning and plasmid transformation, which allow investigation of these inhibitors with more sensitivity than ever before.

Read the article here.

References:
1. Horley, N. J., Beresford, K. J. M., Chawla, T., McCann, G. J. P., Ruparelia, K. C., Gatchie, L., et al. 2017. Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: Overcoming cisplatin resistance in CYP1B1-overexpressing lines. European Journal of Medicinal Chemistry 129: 159-174.

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