Dr. El Sayedresearch group is a molecular target-oriented group discoveringrecurrence-metastasis suppressors based on natural product scaffolds, mergingtraditional natural products, advanced medicinal chemistry-drug design andmolecular pharmacology themes.
Dr. El Sayed group is currentlydeveloping a natural product PCSK9 axis modulator for the control of metastaticprostate cancer recurrence, NCI award R21CA263290. Dr. El Sayed group reported the fermentation spiro-γ-lactamalkaloid pseurotin A (PS) as a first-in-class small-molecule novel proproteinconvertase subtilisin klexin-9 (PCSK9)-LDLR interaction inhibitor, for theprevention of metastatic castration-resistant prostate cancer (mCRPC)recurrence. PCSK9 recently identified as a prospective cancer driver. PS suppressed CRPC recurrence in nude micemodel. PS can be developed as effective recurrence preventer in mCRPCsurvivors.
Cellularlysine methylation driven by protein lysine methyltransferases like the SET andMYND-containing protein (SMYD) enzymes family, play important cellular regulatoryroles SMYD2 methylates several histone and non-histone proteins. SMYD2 dysregulatedin metastatic prostate cancer patients with high Gleason score and shorterdisease-free survival. Epidemiologically, the Mediterranean extra-virgin oliveoil (EVOO)-rich diet correlated with reduced incidence of certain tumors. S-(-)-Oleocanthal (OC) is a naturalphenolic exclusive in EVOO. We validated the molecular target of OC as SMYD2direct inhibitor/expression suppressor, and protein-protein interactions inhibitor.OC can also prevent or delay the PC differentiation of cancers to the fataneuroendocrine phenotype. OC is privileged over the known SMYD2 inhibitors withpotent in vivo potency and high safety profile. OC can be used as effectivenutraceutical to control cancer recurrence without the need for FDA approval.
Thetryptophan-degrading enzymes 2,3-indoleamine dioxygenase (IDO1) and tryptophandioxygenase (TDO2) are dysregulated in metastatic-recurrent cancers. Tryptophan catabolism by IDO1/TDO2 via kynurenine (Kyn) pathway playimportant roles in neurotransmission, immunity, and oncogenesis. We hypothesizedtryptophan oxidative catabolism as a novel molecular target directly drivingcancer motility and recurrence. Dr. El Sayed group recently reported naturalIDO1/TDO2 modulators with excellent PC recurrence preventive potency, includingtobacco cembranoids. (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol(β-CBT) and its C-4 epimer α-CBT are the precursors to key flavor ingredientsin tobacco leaves. Nearly >50% of β- and α-CBT are purposely degraded duringcommercial tobacco fermentation. β-CBT potently suppressed in vivo locoregionaland distant recurrences via suppressing IDO1, TDO2, and Kyn levels. β-CBTemerges as a promising PC recurrence suppressive nutraceutical entity.
Education:
B.S. 1983 Pharmacy,Mansoura University, Egypt. M.Sc. 1989 Pharmacognosy, Mansoura University,Egypt. Ph.D. 1993 Pharmacognosy,Mansoura University, Egypt. 1995-1998 Postdoctoral Research Associate,Department of Pharmacognosy, University of Mississippi. 2000-2001 ResearchAssociate, Department of Pharmacognosy, University of Mississippi.
• ORCIDidentifier: 0000-0002-1456-4064
• MyNCBILink: https://www.ncbi.nlm.nih.gov/myncbi/1Z7fuiqv7iGQj/bibliography/public/
Selected Publications, representativesout of 167:
1. Abdelwahed KS, Siddique AB, Ebrahim HY, Qusa MH,Mudhish EA, Rad AH, Zerfaoui M, Abd Elmageed ZY, El Sayed KA. Pseurotin Avalidation as a metastatic castration-resistant prostate cancerrecurrence-suppressing lead via PCSK9-LDLR axis modulation. Marine Drugs. 2023,21, 215. https://doi.org/10.3390/md21040215.
2. Qusa MH, Abdelwahed KS, Hill RA, El Sayed KA.S-(−)-Oleocanthal ex vivo modulatory effects on gut microbiota. Nutrients 2023,15, 618. https://doi.org/10.3390/nu15030618.
3.McGehee OC, Ebrahim HY, Rad AH,Abdelwahed KS, Mudhish EA, King JA, Helal IE, Meyer SA, El Sayed KA. Towardsdeveloping novel prostate cancer recurrence suppressors: Acute toxicity ofpseurotin A, an orally active PCSK9 axis-targeting small-molecule in Swissalbino mice. Molecules 2023, 28, 1460. https://doi.org/10.3390/molecules28031460.
4. Siddique A, Tajmim A, King J, Ebrahim HY, AbdelwahedK, Abd Elmageed ZY, El Sayed KA. Oleocanthal attenuates metastaticcastration-resistant prostate cancer progression and recurrence by targetingSMYD2. Cancers 2022, 14, 3542.
5. Mudhish EA, Siddique A, Ebrahim HY, AbdelwahedKS, King JA, El Sayed KA. The tobacco β-cembrenediol: A promising prostate cancerrecurrence suppressor lead via modulation of indoleamine 2,3-dioxygenase andtryptophan dioxygenase. Nutrients, 2022;14(7):1505. doi:10.3390/nu14071505
6. Abdelwahed KS, Siddique AB, Mohyeldin MM, Qusa MH,Goda AA, Singh SS, Ayoub NM, King JA, Jois SD, El Sayed KA. Pseurotin A as anovel suppressor of hormone dependent breast cancer progression and recurrenceby inhibiting PCSK9 secretion and interaction with LDL receptor. Pharmacol.Res. 2020, 158, 104847.
• “Topics” (Keywords/Tags): Naturalproducts, olive phenolics, PCSK9, prostate cancer, pseurotins, recurrence, SMYD2,tobacco cembranoids, tryptophan catabolism.
