FNC: An Advanced Anticancer Therapeutic or Just an Underdog?

Abstract

Azvudine (FNC) is a novel cytidine analogue that has both antiviral and anticancer activities. This minireview focuses on its underlying molecular mechanisms of suppressing viral life cycle and cancer cell growth and discusses applications of this nucleoside drug for advanced therapy of tumors and malignant blood diseases. FNC inhibits positive-stand RNA viruses, like HCV, EV, SARS-COV-2, HBV, and retroviruses, including HIV, by suppressing their RNA-dependent polymerase enzymes. It may also inhibit such enzyme (reverse transcriptase) in the human retrotransposons, including human endogenous retroviruses (HERVs). As the activation of retrotransposons can be the major factor of ongoing cancer genome instability and consequently higher aggressiveness of tumors, FNC has a potential to increase the efficacy of multiple anticancer therapies. Furthermore, FNC also showed other aspects of anticancer activity by inhibiting adhesion, migration, invasion, and proliferation of malignant cells. It was also reported to be involved in cell cycle arrest and apoptosis, thereby inhibiting the progression of cancer through different pathways. To the date, the grounds of FNC effects on cancer cells are not fully understood and hence additional studies are needed for better understanding molecular mechanisms of its anticancer activities to support its medical use in oncology.

Keywords: FNC; azvudine; cancer; nucleoside (acid) analogues; oncology.

Figure 1

2′-Deoxy-2′-β-fluoro-4′-azidocytidine (FNC) structure.

Figure 2

(A) Schematic representation of retrotransposon/HERV life cycle; (B) Mechanism of FNC-triggered chain termination. The 3′-OH group of FNC is unlikely to be used by polymerases for elongation of proviral RNA synthesis.; (C) Representation of antitumor mehanisms of FNC through multiple molecular pathways. FNC promotes apoptosis by decreasing Bcl-xL and Bcl-2 and activation of caspase-3 which further regulates proteolytic cleavage of many key proteins such as PARP. FNC inhibits the adhesion, migration and invasion of Raji and JeKo-1 cell lines by up-regulating the expression of E-cadherin and GSK-3β proteins and down-regulating the expression of proteins such as β-catenin, VEGF, MMP-2 and MMP-9. Wnt/β-catenin signaling pathway has a crucial position in the development and promotion of a wide variety of cancers. Activated Wnt/β-catenin changing the E-cadherin-β-catenin complex expression is significantly coupled with the invasiveness of tumor cells. FNC is a cell cycle-nonspecific agent which causes G1/S or G2/M phase cell cycle arrest and induces apoptosis. It inhibits cell cycle checkpoint activation (e.g., Cyclin-A binding to CDK2 permits cells to complete S phase and enter to M phase); (D) Graphic Abstract, depicts the possible mechanisms of FNC anticancer and antiviral activities.