Enediynes: Exploration of microbial genomics to discover new anticancer drug leads

Abstract

The enediyne natural products have been explored for their phenomenal cytotoxicity. The development of enediynes into anticancer drugs has been successfully achieved through the utilization of polymer- and antibody–drug conjugates (ADCs) as drug delivery systems. An increasing inventory of enediynes would benefit current application of ADCs in many oncology programs. Innovations in expanding the enediyne inventory should take advantage of the current knowledge of enediyne biosynthesis and post-genomics technologies. Bioinformatics analysis of microbial genomes reveals that enediynes are underexplored, in particular from Actinomycetales. This digest highlights the emerging opportunities to explore microbial genomics for the discovery of novel enediyne natural products.

Genome neighborhood network reveals insights into enediyne biosynthesis and facilitates prediction and prioritization for discovery

“…Analysis of these microbial genomes illustrates that the biosynthetic potential of bacteria, especially Actinobacteria (921 and 3035 in GenBank and JGI, respectively), is greatly underappreciated. The enediynes are no exception: a recent virtual survey revealed a total of 61 enediyne biosynthetic gene clusters, 54 of which are from the order Actinomycetales [45]. Ten of these gene clusters (NCS [31], C-1027 [30], KED [32], MDP [52], SPO [34], CYA [25], CYN [25], CAL [1], ESP [partial] [29,54], and DYN [14]) are responsible for the biosynthesis of known enediynes.…”

Synergistic Anti-glioma Effects <i>in Vitro</i> and <i>in Vivo</i> of Enediyne Antibiotic Neocarzinostatin and Paclitaxel <i>via</i> Enhanced Growth Delay and Apoptosis-Induction

“…However, recurrences result from the resistances to chemotherapy and radiation has been the great challenges of glioma patients. 2,14) To overcome these limitations, novel chemotherapies or combination treatments are drawing great gravitation to preclinical and clinical research. Enediyne antibiotics, a group of DNAcleaving natural product, have been proposed for treatment of various human cancers, especially NCS, has been an effective and novel chemotherapeutic agent to nervous system cancer, 43) therefore, our study was designed to test the combinational effects of NCS plus PTX.…”

“…Although the malignance of glioma urgently promoted the developments of some attractive medicinal strategies, including targeting therapy, gene therapy and immunotherapy, the first-line strategies of glioma therapy are still mainly alkylating agents concomitant or after radiotherapy, [10][11][12][13] nevertheless, the consequential low sensitivities or intolerance to novel therapies and the multi-drugs resistance (MDR) to the chemotherapy have badly stroked the patients' expectation, which drove more efforts to pressingly pursue the effective and feasible clinic strategies. 2,14) Enediyne antibiotic is a group of natural agents produced by microbial metabolism with potential anti-tumoral effects. At present, enediyne antibiotics are the most potent in currently known anti-tumoral agents.…”

Genome Mining of Micromonospora yangpuensis DSM 45577 as a Producer of an Anthraquinone-Fused Enediyne

“…3,6 Although too toxic for direct use as chemotherapeutic agents, the enediynes have proven highly efficacious for anticancer therapy when delivered using polymer-based or antibody-directed systems. NCS as a polymer drug conjugate (SMANCS) has been marketed since 1994 for the treatment of certain types of leukemia and hepatoma.…”

“…Other ADCs using C-1027 (also known as lidamycin) 8 and UCM as payloads are currently in various stages of preclinical and clinical studies. 6 It is remarkable that four of the 12 known enediynes have been translated into clinical drugs or are in preclinical development, representing an extraordinary success rate of 33%.…”