Effect of a Novel Antidepressant and Anticancer Nuc01 on Depression in Cancer Survivors

Abstract

Depression in cancer survivors is commonly treated with serotonin and norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine. These drugs alleviate depressive symptoms by inhibiting the reuptake of serotonin and norepinephrine. However, a novel approach has emerged with the development of trans-2-phenylcyclopropylamine (PCPA)-drug conjugates that inhibit lysine-specific demethylase 1 (LSD1), which is a biomarker and molecular target for cancer therapy. LSD1 inhibition can effectively suppress cancer cell proliferation. Nuc01 is a novel PCPA-drug conjugate designed as a prodrug of venlafaxine. In vivo studies showed that Nuc01 dose-dependently reduced immobility time in the tail suspension test in mice, outperforming desmethylvenlafaxine. This suggests that Nuc01 may act as a potent triple reuptake inhibitor, potentially offering enhanced efficacy in the treatment of depression. Additionally, in vitro studies demonstrated that Nuc01 effectively occupies the PCPA binding site within LSD1 (IC₅₀ = 530 nm) and inhibits the proliferation of MDA-MB-231 cancer cells (IC₅₀ = 1130 nm). These findings suggest that Nuc01 may function as an LSD1 inhibitor with potential anticancer properties. Collectively, the data indicate that Nuc01 appears to exhibit dual functional characteristics: acting as a triple reuptake inhibitor potentially applicable for depression treatment and as an LSD1 inhibitor demonstrating anticancer potential.

Keywords: LSD1 inhibitor; PCPA–desvenlafaxine conjugate; anticancer; antidepressant.

Figure 1

Prodrug activation mechanism for releasing the small-molecule drug in the PCPA–tamoxifen conjugates designed by Suzuki et al. [16].

Figure 2

Design concept of the PCPA–desvenlafaxine conjugate (Nuc01) as a small molecule-based drug delivery molecule.

Figure 3

Predicted binding mode of Nuc01. The predicted binding mode of Nuc01. (A) Nuc01 located in the PCPA pocket of LSD1. The LSD1 protein is displayed in surface representation, while the small molecule Nuc01 is shown as cyan sticks. The cofactor FAD, which interacts with Nuc01, is represented as green sticks. The distances between Nuc01 and FAD are indicated by dashed lines. (B) The detailed interactions between Nuc01 and LSD1. All residues of the LSD1 protein that interact with Nuc01 are shown in the figure. Green-colored residues indicate hydrophobic interactions, cyan residues represent polar interactions, and purple arrows denote hydrogen bonds. Green dashed lines indicate π–π stacking interactions, while dark red residues represent negatively charged amino acids.

Figure 4

IC₅₀ curve of Nuc01 against LSD1 at the enzymatic level.

Figure 5

In vitro cytotoxicity assay of various Nuc01-containing drugs on MDA-MB-231 cells.

Figure 6

Antidepressant therapeutic effect of different treatments: vehicle, ODV, and various doses of Nuc01 (7.5, 15, and 30 mg/kg) on the TST in C57BL/6 mice. All results are expressed as the mean ± SD from ten independent experiments (n = 10), and the significance levels are *** p < 0.001, analyzed by a one-way ANOVA with a Tukey’s test.