In Vitro and In Vivo Antitumor Activities of Isothiourea and Cinnamic Acid Derivative with NOS/MCT Inhibitory Effect

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• Nitric oxide synthase (NOS) and monocarboxylate lactate transporters (MCT) are implicated in tumor progression.
• Targeting both pathways simultaneously presents a potential strategy for enhanced cancer therapy.
• Developing bifunctional molecules offers a novel approach to cancer treatment.

Purpose of the Study:

• To synthesize and characterize a novel bifunctional inhibitor, T1114, combining NOS and MCT inhibitory fragments.
• To evaluate the in vitro and in vivo cytotoxic and antitumor activities of T1114.
• To investigate the potential of T1114 in overcoming tumor resistance and preventing hypoxic adaptation.

Main Methods:

• Synthesis and physicochemical characterization of α-cyano-4-hydroxycinnamate 1-cyclohexanoyl-2-ethylisothiourea (T1114).
• In vitro cytotoxicity assays.
• In vivo antitumor activity studies in solid Ehrlich carcinoma and RShM-5 mouse cervical cancer models.
• Assessment of tumor microenvironment modulation and hypoxic adaptation.

Main Results:

• T1114 demonstrated comparable in vitro cytotoxic activity to its individual components.
• In vivo, T1114 exhibited significant antitumor effects by inhibiting NOS and MCT.
• The compound prevented hypoxic adaptation in solid Ehrlich carcinoma and overcame resistance in RShM-5 tumors.
• Enhanced antitumor activity was observed due to the combined inhibition of NOS and MCT.

Conclusions:

• The bifunctional NOS/MCT inhibitor T1114 shows promising in vivo antitumor efficacy.
• Combined inhibition of NOS and MCT impacts the tumor microenvironment and hypoxic cells.
• T1114 represents a potential new therapeutic agent for antiangiogenic therapy in malignant neoplasms.
• This strategy offers opportunities to overcome tumor resistance and prevent adaptation.