Abstract
To minimize treatment toxicities, recent anti-cancer research efforts have switched from broad-based chemotherapy to targeted therapy, and emerging data show that altered cellular metabolism in cancerous cells can be exploited as new venues for targeted intervention. In this study, we focused on, among the altered metabolic processes in cancerous cells, altered glycosylation due to its documented roles in cancer tumorigenesis, metastasis and drug resistance. We hypothesize that the enzymes required for the biosynthesis of UDP-hexoses, glycosyl donors for glycan synthesis, could serve as therapeutic targets for cancers. Through structure-based virtual screening and kinetic assay, we identified a drug-like chemical fragment, GAL-012, that inhibit a small family of UDP-hexose pyrophosphorylases-galactose pyro-phosphorylase (GALT), UDP-glucose pyrophosphorylase (UGP2) and UDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1) with an IC50 of 30 µM. The computational docking studies supported the interaction of GAL-012 to the binding sites of GALT at Trp190 and Ser192, UGP2 at Gly116 and Lys127, and AGX1/UAP1 at Asn327 and Lys407, respectively. One of GAL-012 derivatives GAL-012-2 also demonstrated the inhibitory activity against GALT and UGP2. Moreover, we showed that GAL-012 suppressed the growth of PC3 cells in a dose-dependent manner with an EC50 of 75 µM with no effects on normal skin fibroblasts at 200 µM. Western blot analysis revealed reduced expression of pAKT (Ser473), pAKT (Thr308) by 77% and 72%, respectively in the treated cells. siRNA experiments against the respective genes encoding the pyrophosphorylases were also performed and the results further validated the proposed roles in cancer growth inhibition. Finally, synergistic relationships between GAL-012 and tunicamycin, as well as bortezomib (BTZ) in killing cultured cancer cells were observed, respectively. With its unique scaffold and relatively small size, GAL-012 serves as a promising early chemotype for optimization to become a safe, effective, multi-target anti-cancer drug candidate which could be used alone or in combination with known therapeutics.
Highlights
Cancer is one of the leading causes of mortality and morbidity in both developing and developed nations
Recent research efforts have steadily moved from broad-based chemotherapy to targeted therapy to minimize treatment toxicities, and emerging research shows that altered cellular metabolism in cancerous cells can serve as new venues for targeted intervention
We revealed that GAL-012 inhibits two other UDP-hexose pyrophosphorylases exist in humans–UDP-glucose pyro-phosphorylase-2 (UGP2, EC 2.7.7.9) and UDP-N-acetylglucosamine pyrophosphorylase [AGX1/UAP1, EC 2.7.7.23] (Figure 1)
Summary
Cancer is one of the leading causes of mortality and morbidity in both developing and developed nations. Despite significant progress in anti-cancer therapies, some cancers continue to have poor prognosis [2,3]. Recent research efforts have steadily moved from broad-based chemotherapy to targeted therapy to minimize treatment toxicities, and emerging research shows that altered cellular metabolism in cancerous cells can serve as new venues for targeted intervention. Metabolic reprogramming is a hallmark of cancer cells and contributes to their adaption within the tumor microenvironment and resistance to anticancer therapies [4]. Among the altered metabolic processes in cancerous cells, glycosylation has gained increasing attention because of its documented roles in cancer tumorigenesis [5,6], metastasis [7] and drug resistance [8]. Abnormal cancer-specific glycoproteins have been proposed as targets for cancer control [9]
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