Olanzapine, an Atypical Antipsychotic, Inhibits Survivin Expression and Sensitizes Cancer Cells to Chemotherapeutic Agents

Sanomachi, Tomomi; Kuramoto, Kenta; Takeda, Hiroyuki; Sakaki, Hirotsugu; Togashi, Keita; Seino, Shizuka; Yoshioka, Takashi; Okada, Masashi; Kitanaka, Chifumi

doi:10.21873/anticanres.12067

Cited by 24 publications

(32 citation statements)

References 27 publications

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“…GS-Y01 is a CSC line established from a glioblastoma patient [ 35 ]. These CSCs were cultured as previously described [ 34 , 36 ]. In brief, these CSCs were cultured on collagen I-coated dishes (IWAKI, Tokyo, Japan) in stem cell culture medium (DMEM/F12 medium added with 1% B27 supplement (Gibco-BRL, Carlsbad, CA, USA), 20 ng/mL of EGF and FGF2 (PeproTech Inc., Rocky Hill, NJ, USA), D-(+)-glucose (final concentration, 26.2 mM), L-glutamine (final concentration, 4.5 mM), 100 units/mL of penicillin, and 100 μg/mL of streptomycin).…”

Section: Methodsmentioning

confidence: 99%

Doxazosin, a Classic Alpha 1-Adrenoceptor Antagonist, Overcomes Osimertinib Resistance in Cancer Cells via the Upregulation of Autophagy as Drug Repurposing

et al. 2020

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Osimertinib, which is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is an important anticancer drug because of its high efficacy and excellent safety profile. However, resistance against osimertinib is inevitable; therefore, therapeutic strategies to overcome the resistance are needed. Doxazosin, a classic quinazoline-based alpha 1-adrenoceptor antagonist is used to treat hypertension and benign prostatic hyperplasia with a known safety profile. The anticancer effects of doxazosin have been examined in various types of malignancies from the viewpoint of drug repositioning or repurposing. However, it currently remains unclear whether doxazosin sensitizes cancer cells to osimertinib. Herein, we demonstrated that doxazosin induced autophagy and enhanced the anticancer effects of osimertinib on the cancer cells and cancer stem cells of non-small cell lung cancer, pancreatic cancer, and glioblastoma at a concentration at which the growth of non-tumor cells was not affected. The osimertinib-sensitizing effects of doxazosin were suppressed by 3-methyladenine, an inhibitor of autophagy, which suggested that the effects of doxazosin were mediated by autophagy. The present study provides evidence for the efficacy of doxazosin as a combination therapy with osimertinib to overcome resistance against osimertinib.

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Section: Methodsmentioning

confidence: 99%

Doxazosin, a Classic Alpha 1-Adrenoceptor Antagonist, Overcomes Osimertinib Resistance in Cancer Cells via the Upregulation of Autophagy as Drug Repurposing

et al. 2020

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“…TCAs have largely been replaced by selective serotonin reuptake inhibitors, which have a favorable side effect profile. We previously reported the anti-cancer effects of aripiprazole and olanzapine, which are used for cancer patients with fewer side effects [24, 25]. However, olanzapine sometimes causes intolerable sedation [12] and aripiprazole causes akathisia [26, 27]; therefore, antipsychotic drugs that have anti-cancer effects with an improved side effect profile are required.…”

Section: Introductionmentioning

confidence: 99%

In vitroandin vivoanti-tumor effects of brexpiprazole, a newly-developed serotonin-dopamine activity modulator with an improved safety profile

et al. 2019

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From the perspective of psycho-oncology, antipsychotics are widely used for patients with cancer. Although some antipsychotic drugs have anti-tumor effects, these antipsychotic drugs are not applicable for cancer patients because of their severe side effects. Brexpiprazole, a novel serotonin-dopamine modulator with an improved side effect profile, was developed as a drug that is structurally and pharmacologically related to aripiprazole, which was reported to have anti-cancer effects. However, it remains unknown whether brexpiprazole has anti-cancer effects. In this study, we examined whether brexpiprazole has anti-tumor effects in cancer cells and cancer stem cells (CSCs) of glioblastoma, pancreatic cancer, and lung cancer. Brexpiprazole suppressed cell growth and induced cell death in the cancer cells and the CSCs, and decreased the CSC properties of the CSCs. Brexpiprazole did not exert any cytotoxic effects on non-cancer cells at the anti-cancer effect-inducing concentration. In the cancer cells and the CSCs, brexpiprazole reduced the expression of survivin, an anti-apoptotic protein, whose reduction sensitizes tumor cells to chemotherapeutic reagents. In the preclinical model in which pancreatic CSCs were subcutaneously implanted into nude mice, brexpiprazole suppressed tumor growth, in addition to reducing the expression of Sox2, a marker for CSCs, and survivin. This suggests that brexpiprazole is a promising antipsychotic drug with anti-tumor effects and an improved safety profile.

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“…Aripiprazole, an antipsychotic with excellent safety profile, inhibits survivin probably through Wnt/β-Catenin mediated pathway in CSCs, sensitizing them to standard chemotherapeutic drugs. Similar effect is also produced by another antipsychotic drug, Olanzapine [223,224]. Mithramycin A was found to be effective in reducing stemness of LSCs with the help of SP1 and c-Myc with significant downregulation of survivin expression as well [225].…”

Section: Targeting Factors Promoting Stemness and Key Signaling Pathwaysmentioning

confidence: 73%

Emerging Importance of Survivin in Stem Cells and Cancer: the Development of New Cancer Therapeutics

Warrier

Agarwal

Kumar

2020

Stem Cell Rev and Rep

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Survivin is one of the rare proteins that is differentially expressed in normal and cancer cells and is directly or indirectly involved in numerous pathways required for tumor maintenance. It is expressed in almost all cancers and its expression has been detected at early stages of cancer. These traits make survivin an exceptionally attractive target for cancer therapeutics. Even with these promising features to be an oncotherapeutic target, there has been limited success in the clinical trials targeting survivin. Only recently it has emerged that survivin was not being specifically targeted which could have resulted in the negative clinical outcome. Also, focus of research has now shifted from survivin expression in the overall heterogeneous tumor cell populations to survivin expression in cancer stem cells as these cells have proved to be the major drivers of tumors. Therefore, in this review we have analyzed the expression of survivin in normal and cancer cells with a particular focus on its expression in cancer stem cell compartment. We have discussed the major signaling pathways involved in regulation of survivin. We have explored the current development status of various types of interventions for inhibition of survivin. Furthermore, we have discussed the challenges involving the development of potent and specific survivin inhibitors for cancer therapeutics. Finally we have given insights for some of the promising future anticancer treatments.

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Olanzapine, an Atypical Antipsychotic, Inhibits Survivin Expression and Sensitizes Cancer Cells to Chemotherapeutic Agents

Abstract: Olanzapine may benefit cancer patients not only as an antiemetic for CINV, but also by enhancing the effects of chemotherapeutic agents through down-regulation of survivin, which has been implicated in multidrug chemoresistance.

Cited by 24 publications

References 27 publications

Doxazosin, a Classic Alpha 1-Adrenoceptor Antagonist, Overcomes Osimertinib Resistance in Cancer Cells via the Upregulation of Autophagy as Drug Repurposing

Doxazosin, a Classic Alpha 1-Adrenoceptor Antagonist, Overcomes Osimertinib Resistance in Cancer Cells via the Upregulation of Autophagy as Drug Repurposing

In vitroandin vivoanti-tumor effects of brexpiprazole, a newly-developed serotonin-dopamine activity modulator with an improved safety profile

Emerging Importance of Survivin in Stem Cells and Cancer: the Development of New Cancer Therapeutics

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