Abstract

Simple Summary

   The objective of drug repurposing is to discover novel therapeutic uses
   for established pharmaceuticals. Paroxetine (PX), a commonly prescribed
   antidepressant, has demonstrated promising anticancer properties in
   experimental studies. Nevertheless, its precise role and mechanisms of
   action in triple-negative breast cancer (TNBC) remain incompletely
   elucidated. Our research findings propose that PX may impact TNBC by
   modulating critical molecular pathways, providing significant
   implications for enhancing chemosensitivity and identifying potential
   therapeutic synergies in clinical practice. These findings provide a
   basis for the creation of individualized treatment plans and the
   identification of the most effective therapeutic interventions to
   enhance treatment precision and effectiveness in patients with TNBC.

Abstract

   The strategy of drug repurposing has gained traction in the field of
   cancer therapy as a means of discovering novel therapeutic uses for
   established pharmaceuticals. Paroxetine (PX), a selective serotonin
   reuptake inhibitor typically utilized in the treatment of depression,
   has demonstrated promise as an agent for combating cancer.
   Nevertheless, the specific functions and mechanisms by which PX
   operates in the context of triple-negative breast cancer (TNBC) remain
   ambiguous. This study aimed to examine the impact of PX on TNBC cells
   in vitro as both a standalone treatment and in conjunction with other
   pharmaceutical agents. Cell viability was measured using the
   3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)
   assay, apoptosis was assessed through flow cytometry, and the effects
   on signaling pathways were analyzed using RNA sequencing and Western
   blot techniques. Furthermore, a subcutaneous tumor model was utilized
   to assess the in vivo efficacy of combination therapy on tumor growth.
   The results of our study suggest that PX may activate the
   Ca^2+-dependent mitochondria-mediated intrinsic apoptosis pathway in
   TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by
   inducing cytoprotective autophagy. Additionally, the combination of PX
   and chemotherapeutic agents demonstrated moderate inhibitory effects on
   4T1 tumor growth in an in vivo model. These findings indicate that PX
   may exert its effects on TNBC through modulation of critical molecular
   pathways, offering important implications for improving
   chemosensitivity and identifying potential therapeutic combinations for
   clinical use.

   Keywords: triple-negative breast cancer (TNBC), paroxetine, apoptosis,
   autophagy, PI3K-Akt-mTOR pathway, combination therapy

1. Introduction

   Breast cancer is a prevalent and concerning disease affecting women
   today, with an estimated 1.6 million cases annually and a rising
   incidence [[40]1,[41]2]. It ranks third in mortality after lung cancer
   and colorectal cancer, underscoring its substantial impact on women’s
   health [[42]2]. Triple-negative breast cancer (TNBC) is a molecular
   subtype of breast cancer characterized by the absence of estrogen
   receptors, progesterone receptors, and human epidermal growth factor
   receptor 2 expression [[43]3,[44]4]. TNBC accounts for 15–20% of breast
   cancer cases and is distinguished by its high invasiveness and
   malignancy, presenting a challenging prognosis compared to other
   subtypes [[45]5]. Current treatment modalities for breast cancer
   encompass both localized and systemic approaches, such as surgery and
   chemotherapy [[46]5]. Nevertheless, the effectiveness of chemotherapy
   is constrained, and the development of drug resistance often leads to
   TNBC recurrence and worse patient outcomes [[47]6]. Overcoming these
   obstacles necessitates the exploration of novel therapeutic approaches,
   potentially through synergistic combinations of established
   medications.

   Paclitaxel and anthracycline-based chemotherapy regimens have long been
   established as standard treatment options for patients with TNBC
   [[48]2,[49]7,[50]8]. Among these regimens, doxorubicin (DOX), an
   anthracycline agent, is known to inhibit nucleic acid synthesis through
   DNA intercalation, thereby impeding cancer cell proliferation [[51]9].
   Nevertheless, the efficacy of DOX as a standalone treatment is limited
   by the development of adaptive cellular responses over time, leading to
   the acquisition of drug resistance. TNBC frequently exhibits resistance
   to DOX, leading to the emergence of various multidrug-resistant
   phenotypes in cancer cells [[52]10,[53]11]. Moreover, the application
   of DOX is hindered by multicellular toxicities, particularly cardiac
   toxicity, which limits its anticancer potential [[54]9]. Consequently,
   enhancing the efficacy of DOX is crucial to developing safer treatment
   approaches for TNBC.

   Recently, the complex relationship between cancer and emotional states
   has been found to be more nuanced. Notably, depression has been found
   to exhibit a significant association with various types of cancer,
   including oral and pharyngeal cancers (22–57%), pancreatic cancer
   (33–50%), breast cancer (1.5–46%), and lung cancer (11–44%) [[55]12].
   Particularly noteworthy is the heightened vulnerability of individuals
   with breast cancer to depression, attributed to the profound
   psychological impact of changes in body image, which can ultimately
   compromise both quality of life and prognosis [[56]13]. A survey
   conducted by the American Cancer Society emphasizes the impact of
   depression on adherence to cancer treatment, underscoring the
   importance of psychological interventions for cancer patients
   experiencing depression [[57]14]. The integration of antidepressants as
   a treatment modality plays a significant role in addressing depression
   within the cancer population. A number of studies have suggested
   potential synergy between antidepressants and tamoxifen, possibly
   leading to a reduction in breast cancer recurrence [[58]15,[59]16],
   although Haque et al. presented contrasting perspectives on this matter
   [[60]17]. Considering the intricate interplay between antidepressants
   and anticancer drugs, the fusion of antidepressant interventions with
   inherent anticancer attributes presents a promising avenue to mitigate
   the cascade of adverse effects often associated with cancer treatment
   in individuals with depression [[61]17].

   In recent years there has been an increasing acknowledgment of the