Abstract
Drug repurposing has been proved to be an effective strategy to meet the urgent need for novel anticancer agents for multiple myeloma (MM) treatment. In this work, we aimed to investigate the anticancer effect and mechanism of tricyclic antidepressant nortriptyline (NTP) on the U266 MM cell line. The in vitro inhibitory effect of NTP at various doses and time points was studied. The combination potential of cisplatin-NTP was also investigated. Cell cycle analysis and three flow cytometric apoptosis assays were performed. NTP showed dose- and time-dependent inhibitory effects on the U266 MM cell line. NTP had greater inhibitory effect than cisplatin (IC50 26 µM vs. 40 µM). The cisplatin-NTP combination is antagonistic. In addition to G2/M phase cell cycle arrest, NTP induced apoptosis as indicated by mitochondrial membrane potential and caspase-3 and annexin V assays. NTP has inhibitory and apoptotic effects on U266 MM cells. The cisplatin-NTP combination indicated strong antagonism, which may have significant clinical relevance since antidepressants are commonly employed in adjuvant therapy for cancer patients. Based on these findings, the therapeutic potential of NTP for MM treatment should be investigated with in-depth mechanistic studies and in vivo experiments.
Highlights
Multiple myeloma (MM) is a cancer of plasma cells
The IC50 values of NTP and cis were determined as 26.1 ± 1.0 and 39.8 ± 9.9
Nortriptyline-cisplatin combination is antagonistic Cancer treatment efficiency significantly increases when drugs are used in combination
Summary
Multiple myeloma (MM) is a cancer of plasma cells. It is a complex hematological malignancy in which the interaction of neoplastic B cells with the bone marrow microenvironment plays a critical role in the progression of the disease. A high rate of relapse, especially due to multidrug resistance, requires the addition of new drugs to existing chemotherapy strategies. Tricyclic antidepressants (TCAs) belong to a broad class of psychoactive drugs. They show potent in vitro and in vivo anticancer effects on a large variety of tumor cells such as colon, osteosarcoma, prostate, glioma, skin squamous carcinoma, and MM (Frick and Rapanelli, 2013)
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