Comprehensive Library Of Resveratrol News

Natural Molecules Wrestle With SUMO To Eradicate Cancer

The story is all too familiar.  Researchers say they have developed some synthetic molecule that will cure a disease like diabetes, eradicate cancer, prevent blindness, and to wait another decade or two while it is developed.  The molecule is patented.  It developers dream of the day they become billionaires.  But most affected patients won’t be alive for that day.

A recent screening involving 1,596 compounds related to protein degradation led to the discovery of a synthetic molecule called CPD1.  This molecule suppressed the development of breast, lung and colon cancers in lab animals and improves survival rates.  A startup company has been formed to carry this new drug through trials as a hopeful cure for cancer.  Millions of dollars of capital are being invested.

The target of this drug is the SUMO gene, which when activated promotes cancer.  The SUMO gene makes SUMO enzymes (proteins), in a process called epigenetics.

Up until 2018 no small molecule had been designed to effectively inhibit the SUMO enzyme.  Most SUMO inhibitors display weak anticancer activity.

Undruggable

The SUMO protein has long been considered “undruggable.”

But now a breakthrough.  CPD1 resulted in longer survival in breast, colon and lung implanted human tumors in laboratory mice.  Have we got a cure here?

The process of SUMOylation (modification of proteins by SUMO) is also involved in heart disease, Parkinson’s and Alzheimer’s disease as well as the immune system.  SUMO binding to the amino acid lysine is the main mechanism.

The SUMO gene codes genes to produce proteins.  In turn these enzymes/proteins are involved in cellular repair, programmed cell death (apoptosis) and other cellular processes.

A SUMO-activating enzyme is involved in the growth and spread of cancer.  Destruction or inhibition of SUMO gene protein is considered an emerging, novel and promising therapeutic target for cancer.

The natural enzyme inhibitors

While interest in molecular SUMO degraders is now piqued, natural small molecules like the red wine molecule resveratrol have already been demonstrated to inhibit SUMO and cancer.

Another small natural molecule, fisetin derived from strawberries, has been demonstrated to destabilize SUMO proteins via its binding capabilities.

There are currently over 100 enzyme-inhibiting drugs that are currently marketed for the treatment of numerous diseases.

Polyphenolic molecules in nature like resveratrol and fisetin are broad enzyme inhibitors.  In fact, it is said resveratrol and fisetin can molecularly replace many drugs.  Here is a list of some enzyme-inhibiting drugs where resveratrol exhibits similar enzyme inhibition.

ENZYME INHIBITING DRUGS Source: Tissue Engineering & Regenerative Medicine 2019
ENZYME INHIBITOR DRUG	ENZYME TARGET	INHIBITED BY RESVERATROL
Aspirin	Cyclooxygenase	✔
Penicillin	Transpeptidase	✔
Allopurinol (gout)	Xanthine oxidase	✔
Statin drugs (cholesterol)	HMG-CoA reductase	✔
Viagra (impotence)	Phosphodiesterase	✔
Gleevec (diabetes)	Bcr-Abl kinase	✔
Tacrine (Alzheimer’s)	Acetylcholinesterase	✔
Finasteride (prostate)	Steroid 5a-reductase	✔
Valproic acid (bipolar)	UDP-glucuronosyltransferases	✔
Ciglitazone (diabetes)	15-Hydroxyprostaglandin	✔
Lisinopril, Enalapril (blood pressure)	Angiotensin-converting enzyme	✔
Carbidopa	Dopa decarboxylase	✔
Emtricitabine (HIV)	Nucleoside reverse transcriptase inhibitor	✔
Selegiline (depression)	Monoamine oxidase	✔