Repurposing Syrosingopine for Cancer Therapy: Lactate Trapping and ISR Sensitization as Metabolic Vulnerabilities

Area of Science:

• Oncology
• Metabolic pathways
• Drug repurposing

Background:

• Cancer cells exhibit aerobic glycolysis (Warburg effect), producing lactate to support tumor growth and immune evasion.
• Syrosingopine, an antihypertensive drug, is repurposed as a dual inhibitor of lactate transporters MCT1 and MCT4.
• This inhibition causes intracellular lactate accumulation and perturbs NAD+ regeneration, inducing bioenergetic stress.

Purpose of the Study:

• To review the repositioning of syrosingopine as a metabolic modulator in oncology.
• To summarize mechanistic insights, preclinical efficacy, and clinical development considerations.
• To highlight immunometabolic effects and synthetic lethality with metabolic inhibitors.

Main Methods:

• A narrative review of English-language publications from 2016-2026 was conducted.
• Studies were identified through PubMed and Scopus, supplemented by manual reference screening.
• Eligible studies focused on syrosingopine in cancer biology, tumor metabolism, immunometabolism, and therapeutic mechanisms.

Main Results:

• Syrosingopine inhibits lactate efflux, reduces glycolytic flux, and depletes NAD+, sensitizing cancer cells to metformin and UK-5099.
• This leads to apoptosis and cell-cycle arrest via a synthetic lethality-like mechanism.
• Advanced delivery systems enhance drug accumulation and remodel the immunosuppressive tumor microenvironment, but context-dependent toxicities exist.

Conclusions:

• Syrosingopine acts as a preclinical "lactate trap" metabolic intervention for glycolysis-dependent tumors.
• It has the potential to modulate integrated stress responses and immunometabolic pathways.
• Successful clinical repurposing requires biomarker-guided trials, optimized formulations, and safety monitoring.