Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), were studied for their potential application in different diseases, especially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from the SSRIs class for the treatment of several neuropsychiatric disorders with a favorable safety profile. FLX exhibited different oncolytic effects via mechanisms distinct from its main serotonergic activity. Taking advantage of its ability to rapidly penetrate the blood–brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of the literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers, highlighting the multifaceted activities of FLX and its ability to interrupt cancer proliferation via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX onto carriers to enhance its safety and efficacy on cancer cells. This is the first review article extensively summarizing all previous FLX repurposing studies for the management of cancer.

Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antide-pressants (TCAs) were studied for their potential application in different diseases es-pecially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from SSRIs class for the treatment of several neuropsychiatric disorders with a favourable safety profile. FLX exhibited different oncolytic effects via mechanisms dis-tinct from its main serotonergic activity. Taking advantage of its ability to rapidly pen-etrate the blood-brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers highlighting the multifaceted activities of FLX and its ability to interrupt cancer prolif-eration via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX on car-riers to enhance its safety and efficacy on cancer cells. This is the first review article ex-tensively summarizing all previous FLX repurposing studies for the management of cancer.

Membrane-bound organelles play important, frequently essential, roles in cellular metabolism in eukaryotes. Hence, cells have evolved molecular mechanisms to closely monitor organelle dynamics and maintenance. The actin cytoskeleton plays a vital role in organelle transport and positioning across all eukaryotes. Studies in the budding yeast Saccharomyces cerevisiae (S. cerevisiae) revealed that a block in actomyosin-dependent transport affects organelle inheritance to daughter cells. Indeed, class V Myosins, Myo2, and Myo4, and many of their organelle receptors, have been identified as key factors in organelle inheritance. However, the spatiotemporal regulation of yeast organelle transport remains poorly understood. Using peroxisome inheritance as a proxy to study actomyosin-based organelle transport, we performed an automated genome-wide genetic screen in S. cerevisiae. We report that the spindle position checkpoint (SPOC) kinase Kin4 and, to a lesser extent, its paralog Frk1, regulates peroxisome transport, independent of their role in the SPOC. We show that Kin4 requires its kinase activity to function and that both Kin4 and Frk1 protect Inp2, the peroxisomal Myo2 receptor, from degradation in mother cells. In addition, vacuole inheritance is also affected in kin4/frk1-deficient cells, suggesting a common regulatory mechanism for actin-based transport for these two organelles in yeast. More broadly our findings have implications for understanding actomyosin-based transport in cells.

Lung adenocarcinoma is a prevalent, aggressive cancer with a poor prognosis due to early metastasis and resistance to treatment. LncRNA AFAP1-AS1 has been shown to be associated with the development of multiple carcinomas. This study investigates the functional role of AFAP1-AS1 in lung adenocarcinoma cell proliferation via miR-508-3p and ZWINT. Human lung adenocarcinoma A549 cells were transfected with siRNA constructs against AFAP1-AS1 (si-AFAP1-AS1) to silence its expression. Cell proliferation was evaluated via CCK-8 and colony-forming assays. Apoptosis was assessed using AO/EB staining, and invasion was determined via Transwell assay. The interaction between AFAP1-AS1, miR-508-3p, and ZWINT was confirmed via dual luciferase reporter assay and qRT-PCR analysis. Data were analysed using appropriate statistical tests. AFAP1-AS1 was significantly upregulated in lung adenocarcinoma cells compared to normal BEAS-2B cells. Silencing of AFAP1-AS1 resulted in a marked reduction in A549 cell proliferation and colony development, as observed in CCK-8 and colony formation assays. The AO/EB assay showed a significant increase in apoptosis (30 ± 4.4%) in si-AFAP1-AS1 transfected cells compared to control si-NC (3 ± 1.2%). In addition, knockdown of AFAP1-AS1 led to an upsurge of pro-apoptotic Bax and decline of anti-apoptotic Bcl-2 expression. The dual luciferase assay established the interaction between AFAP1-AS1 and miR-508-3p. Furthermore, ZWINT, identified as a target of miR-508-3p, was significantly upregulated in lung adenocarcinoma tissues. Overexpression of ZWINT rescued the inhibitory effects of AFAP1-AS1 silencing on cell proliferation, colony formation, and apoptosis, while also reversing the reduction in cell invasion. AFAP1-AS1 accelerates the development of lung adenocarcinoma by cell proliferation, apoptosis, and invasion via the miR-508-3p/ZWINT axis. Thus, targeting AFAP1-AS1 or its downstream regulatory axis could offer novel therapeutic approaches in lung adenocarcinoma treatment.

Pancreatic cancer (PC) is considered one of the most challenging and formidable malig-nancies to treat because it is usually diagnosed at terminal stage, thus it is characterized with a poor prognosis with 5% of patients living over 5 years. The late diagnosis leads to a lower suc-cess rate of resectability, hence chemotherapy or chemoradiotherapy are the only hopes for most PC patients. However, the available drug combinations for PC treatment did not provide satisfactory clinical outcomes. There is a pressing and urgent need to discover new chemothera-peutics which fight PC with tolerable side effects and less liability for resistance. Pentacyclic triterpenes (PTs) are privileged structures with a multitude of biological activities mitigating several ailments, particularly in neoplasm field. They are characterized by a high therapeutic window and their activity can be highly enhanced through structural modifications. Indeed, several parent PTs such as oleanolic acid, ursolic acid, lupeol, betulinic acid, and celastrol proved effective against different PC phenotypes inhibiting their proliferation, invasion, and metastasis mainly via KRAS modulation. Some PTs worked as adjuvant chemosensitizers in gemcitabine-resistant or TRAIL-resistant cells. Owing to their potential in PC treatment, we pre-sent this review article summarizing PC pathogenesis and the promising role of PTs in the man-agement of PC when used either solely or in combination with other chemotherapies such as gemcitabine and 5-Fluorouracil.