Search Results (2)

Glioblastoma multiforme (GBM) is among the most lethal primary brain tumors and is characterized by significant cellular heterogeneity and resistance to conventional therapies. This study investigates the efficacy of seco-duocarmycin SA (seco-DSA), a novel DNA alkylating agent. Initial investigations using a colony formation assay revealed that seco-DSA exhibits remarkable potential with IC₅₀ values lower than its natural DSA counterpart. Cell viability assay indicated that LN18 cells showed a markedly greater sensitivity to DSA than T98G cells. Furthermore, seco-DSA achieved its full cytotoxic effect within 8 h of drug incubation in GBM cell lines. Although seco-DSA induced a concentration-dependent increase in apoptotic cell death, the extent of apoptosis did not fully account for the observed decrease in cell viability. Instead, seco-DSA treatment resulted in significant cell cycle arrest in S and G2/M phases. These findings suggest that seco-DSA’s cytotoxicity in GBM cells is primarily due to its ability to disrupt cell cycle progression, though the precise mechanisms of action remain to be fully established, and further research is needed. Proteomic analysis of treated cells also indicates dysregulation of proteins involved in senescence, apoptosis, and DNA repair, alluding to seco-DSA-induced arrest as a major mechanism of GBM disruption. Data are available via ProteomeXchange with the dataset identifier “PXD061023”. Our reports promote the future exploration of seco-DSA’s therapeutic potential, representing a critical step toward developing a more targeted and effective treatment for GBM. Full article

The duocarmycin family is a group of potent cytotoxic agents originally isolated from the bacterium Streptomyces. This discovery has spurred significant interest due to duocarmycins’ unique chemical structures and powerful mechanism of action. This review comprehensively details the history of the duocarmycin family, the current understanding of their therapeutic potential, and the major clinical trials that have been conducted. Chemically, the duocarmycin family is characterized by a DNA-binding unit that confers specificity, a subunit-linking amide that positions the molecule within the DNA helix, and an alkylating unit that interacts with the DNA. This configuration allows them to bind selectively to the minor groove of DNA and alkylate adenine bases, a notable deviation from the more common guanine targeting performed by other alkylating agents. Duocarmycin’s mechanism of action involves the formation of covalent adducts with DNA, leading to the disruption of the DNA architecture and subsequent inhibition of replication and transcription. Recent advancements in drug delivery systems, such as antibody–drug conjugates (ADCs), have further elevated the therapeutic prospects of duocarmycin analogs by providing a promising mechanism for enhancing intracellular concentrations and selective tumor delivery. Preclinical studies have highlighted the efficacy of duocarmycin derivatives in various in vitro models, providing a strong foundation for translational research. However, further biological research is required to fully understand the toxicology of duocarmycin family members before it can be clinically relevant. The major focus of this review is to cache the major biologically relevant findings of different duocarmycin analogs as well as their biological shortcomings to propose next steps in the field of cancer therapy with these potent therapeutics. Full article