Women with aggressive triple-negative breast cancer (TNBC) are at high risk of brain metastasis, which has no effective therapeutic option partially due to the poor penetration of drugs across the blood−brain barrier. Trifluoperazine (TFP) is an approved antipsychotic drug with good bioavailability in brain and had shown anticancer effect in several types of cancer. It drives us to investigate its activities to suppress TNBC, especially the brain metastasis. In this study, we chose three TNBC cell lines MDA-MB-468, MDA-MB-231, and 4T1 to assess its anticancer activities along with the possible mechanisms. In vitro, it induced G0/G1 cell cycle arrest via decreasing the expression of both cyclinD1/CDK4 and cyclinE/CDK2, and stimulated mitochondria-mediated apoptosis. In vivo, TFP suppressed the growth of subcutaneous xenograft tumor and brain metastasis without causing detectable side effects. Importantly, it prolonged the survival of mice bearing brain metastasis. Immunohistochemical analysis of Ki67 and cleaved caspase-3 indicated TFP could suppress the growth and induce apoptosis of cancer cells in vivo. Taken together, TFP might be a potential available drug for treating TNBC with brain metastasis, which urgently needs novel treatment options.

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Repurposing existing drugs for cancer treatment is an effective strategy. An approved antipsychotic drug, trifluoperazine (TFP), has been reported to have potential anticancer effects against several cancer types. Here, we investigated the effect and molecular mechanism of TFP in colorectal cancer (CRC). In vitro studies showed that TFP induced G0/G1 cell cycle arrest to dramatically inhibit CRC cell proliferation through downregulating cyclin-dependent kinase (CDK) 2, CDK4, cyclin D1, and cyclin E and upregulating p27. TFP also induced apoptosis, decreased mitochondrial membrane potential, and increased reactive oxygen species levels in CRC cells, indicating that TFP induced mitochondria-mediated intrinsic apoptosis. Importantly, TFP significantly suppressed tumor growth in two CRC subcutaneous tumor models without side effects. Interestingly, TFP treatment increased the expression levels of programmed death-1 ligand 1 (PD-L1) in CRC cells and programmed death-1 (PD-1) in tumor-infiltrating CD4+ and CD8+ T cells, implying that the combination of TFP with an immune checkpoint inhibitor, such as an anti-PD-L1 or anti-PD-1 antibody, might have synergistic anticancer effects. Taken together, our study signifies that TFP is a novel treatment strategy for CRC and indicates the potential for using the combination treatment of TFP and immune checkpoint blockade to increase antitumor efficiency.

Ferroptosis is an iron-dependent regulated form of cell death caused by excessive lipid peroxidation. This form of cell death differed from known forms of cell death in morphological and biochemical features such as apoptosis, necrosis, and autophagy. Cancer cells require higher levels of iron to survive, which makes them highly susceptible to ferroptosis. Therefore, it was found to be closely related to the progression, treatment response, and metastasis of various cancer types. Numerous studies have found that the ferroptosis pathway is closely related to drug resistance and metastasis of cancer. Some cancer cells reduce their susceptibility to ferroptosis by downregulating the ferroptosis pathway, resulting in resistance to anticancer therapy. Induction of ferroptosis restores the sensitivity of drug-resistant cancer cells to standard treatments. Cancer cells that are resistant to conventional therapies or have a high propensity to metastasize might be particularly susceptible to ferroptosis. Some biological processes and cellular components, such as epithelial–mesenchymal transition (EMT) and noncoding RNAs, can influence cancer metastasis by regulating ferroptosis. Therefore, targeting ferroptosis may help suppress cancer metastasis. Those progresses revealed the importance of ferroptosis in cancer, In order to provide the detailed molecular mechanisms of ferroptosis in regulating therapy resistance and metastasis and strategies to overcome these barriers are not fully understood, we described the key molecular mechanisms of ferroptosis and its interaction with signaling pathways related to therapy resistance and metastasis. Furthermore, we summarized strategies for reversing resistance to targeted therapy, chemotherapy, radiotherapy, and immunotherapy and inhibiting cancer metastasis by modulating ferroptosis. Understanding the comprehensive regulatory mechanisms and signaling pathways of ferroptosis in cancer can provide new insights to enhance the efficacy of anticancer drugs, overcome drug resistance, and inhibit cancer metastasis.

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