Microbial Enzymes used in Prodrug Activation for Cancer Therapy: Insights and Future Perspectives

Dhankhar, Rakhi; Kawatra, Anubhuti; Mohanty, Aparajita; Gulati, Pooja

doi:10.2174/1389203721666201207231932

Cited by 9 publications

(4 citation statements)

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“…The drug formed inside the cell causes its death (suicide), and the drug being a small molecular weight compound diffuses into other cells, causing a neighboring killing effect. Several GDEPT systems have been described most of them using microbial enzymes [14]. Generally, the choice of an enzyme and the availability of a suitable prodrug are the major factors determining the success and therapeutic utility of GDEPT.…”

Section: Figure 1 Schematic Diagram Illustrating Suicide Gene Evs Der...mentioning

confidence: 99%

Tumor-targeted suicide gene-directed enzyme prodrug therapy mediated by extracellular vesicles

Jakubechova¹,

Altanerova²,

Altaner³

2023

neo

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In this article, we describe the gene-directed enzyme prodrug therapy, also known as the "Trojan Horse" therapy mediated by exosomes -small extracellular vesicles (sEVs) secreted from mesenchymal stem/stromal cells (MSCs) and cancer cells. MSC-EVs possess strong migrating tropism toward tumor sites. EVs derived from tumor cells mimic the parental cells in an invasive metastatic growth trait and the capability to reprogram the recipient cells. The behavior of these EVs when modified with the suicide gene predestinates them to be a drug with guided intracellular action. EVs with therapeutic suicide gene are prepared from cells with integrated retrovirus vector containing its genetic message. These EVs are internalized by tumor cells and the product of the gene converts the non-toxic prodrug into a cytotoxic drug inside the cell causing its suicide. The action of two suicide gene systems are described: the yCD::UPRT-MSC/5-FC system and the HSVTK-MSC-GCV system. Suicide gene EVs either MSCs or tumor cell origin due to their intrinsic targeting capabilities, high modification flexibility, as well as biological barrier permeability represent potential drugs for tumors untreatable with present standard cancer therapies.

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Section: Figure 1 Schematic Diagram Illustrating Suicide Gene Evs Der...mentioning

confidence: 99%

Tumor-targeted suicide gene-directed enzyme prodrug therapy mediated by extracellular vesicles

Jakubechova¹,

Altanerova²,

Altaner³

2023

neo

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“…Oncolytic bacteria and viruses, such as Bifidobacteria , Clostridium , Listeria monocytogenes , Salmonella typhimurium , Bacillus , Vaccinia viruses , Adenoviruses , Reoviruses , Herpesviruses , and Coxsackieviruses , have arisen as remarkable therapeutic strategies in the quest for the treatment and potential eradication of malignant tumors [ 69 ]. Due to their inherent anti-cancer properties and ability to interact with tumor microenvironments (TME), these microbes are attractive options for cancer therapy [ 70 , 71 ]. Living viruses were administered to cancer patients in the 1950s and 1970s, which improved their course of treatment or recovery [ 72 , 73 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic bacteria and viruses to combat cancer: double-edged sword in cancer therapy: new insights for future

Yarahmadi,

Zare,

Aghayari

et al. 2024

Cell Commun Signal

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Cancer, ranked as the second leading cause of mortality worldwide, leads to the death of approximately seven million people annually, establishing itself as one of the most significant health challenges globally. The discovery and identification of new anti-cancer drugs that kill or inactivate cancer cells without harming normal and healthy cells and reduce adverse effects on the immune system is a potential challenge in medicine and a fundamental goal in Many studies. Therapeutic bacteria and viruses have become a dual-faceted instrument in cancer therapy. They provide a promising avenue for cancer treatment, but at the same time, they also create significant obstacles and complications that contribute to cancer growth and development. This review article explores the role of bacteria and viruses in cancer treatment, examining their potential benefits and drawbacks. By amalgamating established knowledge and perspectives, this review offers an in-depth examination of the present research landscape within this domain and identifies avenues for future investigation. Graphical Abstract The double-edged sword role of bacteria and viruses in cancer therapy.

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“…Gene-directed enzyme-prodrug therapy (GDEPT) is a precision medicine strategy based on the vector-mediated delivery of a genetically encoded prodrug-converting enzyme to tumor cells [ 1 , 2 , 3 ]. Systemic administration of the prodrug then results in preferential activation of the corresponding toxin in tumors.…”

Section: Introductionmentioning

confidence: 99%

Structural Evaluation of a Nitroreductase Engineered for Improved Activation of the 5-Nitroimidazole PET Probe SN33623

Sharrock,

Mumm,

Williams

et al. 2024

IJMS

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Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell ablation models. We recently engineered a nitroreductase (E. coli NfsB F70A/F108Y) for the substantially enhanced reduction of the 5-nitroimidazole PET-capable probe, SN33623, which permits the theranostic imaging of vectors labeled with oxygen-insensitive bacterial nitroreductases. This mutant enzyme also shows improved activation of the DNA-alkylation prodrugs CB1954 and metronidazole. To elucidate the mechanism behind these enhancements, we resolved the crystal structure of the mutant enzyme to 1.98 Å and compared it to the wild-type enzyme. Structural analysis revealed an expanded substrate access channel and new hydrogen bonding interactions. Additionally, computational modeling of SN33623, CB1954, and metronidazole binding in the active sites of both the mutant and wild-type enzymes revealed key differences in substrate orientations and interactions, with improvements in activity being mirrored by reduced distances between the N5-H of isoalloxazine and the substrate nitro group oxygen in the mutant models. These findings deepen our understanding of nitroreductase substrate specificity and catalytic mechanisms and have potential implications for developing more effective theranostic imaging strategies in cancer treatment.

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Microbial Enzymes used in Prodrug Activation for Cancer Therapy: Insights and Future Perspectives

Cited by 9 publications

References 0 publications

Tumor-targeted suicide gene-directed enzyme prodrug therapy mediated by extracellular vesicles

Tumor-targeted suicide gene-directed enzyme prodrug therapy mediated by extracellular vesicles

Therapeutic bacteria and viruses to combat cancer: double-edged sword in cancer therapy: new insights for future

Structural Evaluation of a Nitroreductase Engineered for Improved Activation of the 5-Nitroimidazole PET Probe SN33623

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