Actinomycetota-Derived Metabolites in Pancreatic Cancer: Chemical Diversity, Metabolic Vulnerability, and Translational Barriers.
9 affiliations
- 1Programa de Pós-Graduação em Ciências Farmacêuticas, Departamento de Farmácia, Universidade Estadual da Paraíba (UEPB), Campina Grande, 58429-500, PB, Brazil.
- 2NuBioCaatinga. Núcleo de Bioprospecção da Caatinga, Universidade Federal do Rio Grande do Norte (UFRN), Santa Cruz, 59200-000, RN, Brazil.
- 3FACISA - Faculdade de Ciências da Saúde do Trairi, Universidade Federal do Rio Grande do Norte (UFRN), Santa Cruz, 59200-000, RN, Brazil.
- 4Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, V6T 1Z3, BC, Canada.
- 5Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba (UFPB), João Pessoa, 58051-900, PB, Brazil.
- 6CiTCoM UMR 8038, Faculté de Santé, Université Paris Cité, Paris, France.
- 7Instituto de Ciências Biológicas e da Saúde (ICBS), Universidade Federal de Alagoas (UFAL), Maceió, 57072-970, AL, Brazil. [email protected].
- 8NuBioCaatinga. Núcleo de Bioprospecção da Caatinga, Universidade Federal do Rio Grande do Norte (UFRN), Santa Cruz, 59200-000, RN, Brazil. [email protected].
- 9FACISA - Faculdade de Ciências da Saúde do Trairi, Universidade Federal do Rio Grande do Norte (UFRN), Santa Cruz, 59200-000, RN, Brazil. [email protected].
Abstract
Purpose of review
Pancreatic ductal adenocarcinoma remains among the deadliest malignancies worldwide, and effective therapies are still lacking. Actinomycetota are among the richest microbial sources of bioactive secondary metabolites, and three agents in clinical use against pancreatic malignancy derive from them - streptozotocin, everolimus and doxorubicin - though all three are indicated for neuroendocrine rather than ductal tumors. This review provides a critical narrative synthesis of Actinomycetota-derived metabolites evaluated in pancreatic cancer models, with every potency value re-derived from the primary literature and interpreted alongside assay conditions and available mechanistic and in vivo evidence.Recent findings
Fifty-two compounds from 25 primary reports encompass polyketides, nonribosomal peptides, depsipeptides, RiPPs, alkaloids, ionophores and hybrid scaffolds. Rather than a simple ranking of increasingly potent cytotoxins, the literature poses a sharper question about selectivity. Two compounds are conditionally active: kigamicin D only under nutrient deprivation and BE-43547A₂ only under hypoxia, exploiting the metabolic state that defines the disease rather than any intrinsic difference between malignant and normal cells. Both were recovered by screens built to detect that behavior, and neither has been shown to hold a therapeutic window in vivo. Separately, thiogochangamide B retains activity in gemcitabine-resistant models, while trienomycin A binds STAT3 directly, suppresses proliferation across eight pancreatic lines, achieves 84-98% tumor growth inhibition in xenografts at doses producing no detectable toxicity, and distributes preferentially to pancreatic tissue. Conditional activity is best read as a hypothesis about how such compounds should be sought rather than as an established route to selectivity. Despite remarkable chemical diversity, translation remains constrained by the limited use of normal-cell controls, predictive biomarkers and clinically relevant preclinical models. Screens conducted in nutrient-replete, normoxic monolayer culture will systematically miss compounds of this kind. Future efforts should prioritize compounds that exploit the metabolic liabilities of pancreatic cancer rather than pursuing greater cytotoxic potency.
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BibTeX
@article{lima2026actinomycetotaderived,
title = {{Actinomycetota-Derived Metabolites in Pancreatic Cancer: Chemical Diversity, Metabolic Vulnerability, and Translational Barriers.}},
author = {Daynara da Silva Pereira Lima and Marcelly da Silveira Silva and Moisés da Rocha Soares and Lucas Evangelista Lima Terceiro and Natanael Teles Ramos de Lima and Genil Dantas de Oliveira and Thalisson Amorim de Souza and Valnês Silva Rodrigues-Junior and Samuel Paulo Cibulski},
journal = {Current oncology reports},
year = {2026},
month = oct,
doi = {10.1007/s11912-026-01842-y},
url = {https://europepmc.org/article/MED/42873463},
note = {CC BY},
}
RIS
TY - JOUR
TI - Actinomycetota-Derived Metabolites in Pancreatic Cancer: Chemical Diversity, Metabolic Vulnerability, and Translational Barriers.
AU - Daynara da Silva Pereira Lima
AU - Marcelly da Silveira Silva
AU - Moisés da Rocha Soares
AU - Lucas Evangelista Lima Terceiro
AU - Natanael Teles Ramos de Lima
AU - Genil Dantas de Oliveira
AU - Thalisson Amorim de Souza
AU - Valnês Silva Rodrigues-Junior
AU - Samuel Paulo Cibulski
PY - 2026
DA - 2026/10/14
JO - Current oncology reports
DO - 10.1007/s11912-026-01842-y
UR - https://europepmc.org/article/MED/42873463
AB - Purpose of review Pancreatic ductal adenocarcinoma remains among the deadliest malignancies worldwide, and effective therapies are still lacking. Actinomycetota are among the richest microbial sources of bioactive secondary metabolites, and three agents in clinical use against pancreatic malignancy derive from them - streptozotocin, everolimus and doxorubicin - though all three are indicated for neuroendocrine rather than ductal tumors. This review provides a critical narrative synthesis of Actinomycetota-derived metabolites evaluated in pancreatic cancer models, with every potency value re-derived from the primary literature and interpreted alongside assay conditions and available mechanistic and in vivo evidence.Recent findings Fifty-two compounds from 25 primary reports encompass polyketides, nonribosomal peptides, depsipeptides, RiPPs, alkaloids, ionophores and hybrid scaffolds. Rather than a simple ranking of increasingly potent cytotoxins, the literature poses a sharper question about selectivity. Two compounds are conditionally active: kigamicin D only under nutrient deprivation and BE-43547A₂ only under hypoxia, exploiting the metabolic state that defines the disease rather than any intrinsic difference between malignant and normal cells. Both were recovered by screens built to detect that behavior, and neither has been shown to hold a therapeutic window in vivo. Separately, thiogochangamide B retains activity in gemcitabine-resistant models, while trienomycin A binds STAT3 directly, suppresses proliferation across eight pancreatic lines, achieves 84-98% tumor growth inhibition in xenografts at doses producing no detectable toxicity, and distributes preferentially to pancreatic tissue. Conditional activity is best read as a hypothesis about how such compounds should be sought rather than as an established route to selectivity. Despite remarkable chemical diversity, translation remains constrained by the limited use of normal-cell controls, predictive biomarkers and clinically relevant preclinical models. Screens conducted in nutrient-replete, normoxic monolayer culture will systematically miss compounds of this kind. Future efforts should prioritize compounds that exploit the metabolic liabilities of pancreatic cancer rather than pursuing greater cytotoxic potency.
SN - 1523-3790
SN - 1534-6269
ER -