Apratoxin S10 as a dual-action modulator of receptor tyrosine kinases and tumor microenvironment: emerging anticancer insights from marine-derived analogs.

Abstract

Marine cyanobacteria are prolific producers of structurally diverse and pharmacologically potent secondary metabolites. Among these, apratoxins, a class of cyclodepsipeptides originally isolated from Lyngbya species have demonstrated broad-spectrum cytotoxic and antiangiogenic activity. However, the clinical development of natural apratoxins has been limited due to systemic toxicity and narrow therapeutic indices. Recent efforts have focused on optimizing these molecules, leading to the development of semi-synthetic analogs such as Apratoxin S10 (Apra S10), which exhibits improved stability, selectivity, and potency. This review synthesizes current evidence on the anticancer mechanisms of Apra S10 and related apratoxins, including their effects on receptor tyrosine kinases (RTKs), growth factor signaling, and tumor microenvironment modulation. Emphasis is placed on Apra S10's preclinical pharmacokinetics, tumor-specific accumulation, and multi-target activity across highly vascularized tumors, including hepatocellular carcinoma, renal cell carcinoma, neuroendocrine tumors, and pancreatic ductal adenocarcinoma. Studies show that Apra S10 downregulates RTKs, suppresses secretion of VEGF-A and IL-6, and disrupts tumor-stroma crosstalk, mechanisms that collectively result in potent growth inhibition and antiangiogenic effects without overt toxicity. These findings highlight Apra S10 and its analogs as promising candidates for adjuvant cancer therapy, meriting further translational research to assess clinical safety, pharmacodynamics, and synergistic potential with existing chemotherapeutics.