Trifluoperazine induces cellular apoptosis by inhibiting autophagy and targeting NUPR1 in multiple myeloma

Li, Anmao; Chen, Xuanxin; Jing, Zizi; Chen, Jianbin

doi:10.1002/2211-5463.12960

Cited by 22 publications

(21 citation statements)

References 28 publications

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“…Exposure to TFP or its derivatives was previously reported to result from either induction of autophagy [ 11 , 24 ] or interruption of autophagy flux [ 19 , 25 ], leading to opposite cellular outcomes. To determine whether TFP influences autophagy, PAH-PASMCs were first observed under a bright-field phase-contrast microscope.…”

Section: Resultsmentioning

confidence: 99%

“…However, in numerous circumstances, autophagy functions as a double-edged sword as both excessive or insufficient levels of autophagic flux can affect cell viability and precipitate cell death [ 32 ]. Although TFP was reported to exert anti-proliferative and anti-survival effects in multiple cancer models [ 12 , 18 , 19 , 25 , 33 ], conflicting data exist regarding the impact of TFP on autophagy and its consequence on cell viability [ 19 , 24 , 34 , 35 ]. Herein, we showed that anti-proliferative and anti-survival effects of TFP were accompanied by induction of autophagy.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension

Grobs

Awada

Lemay

et al. 2021

IJMS

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Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension

Grobs

Awada

Lemay

et al. 2021

IJMS

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show abstract

“…25 In most cases, autophagy plays an anti-apoptotic role by raising the stress threshold required for the induction of apoptosis, or by directly suppressing apoptosis. 17,26,27 However, in rare cases, excessive autophagy can lead to ACD of tumour cells due to the extreme degradation of the organelles and cytoplasm. 28,29 In the present study, using RNA-seq, we found that autophagy-related genes were transcriptionally activated by SM in H929 cells (Figure 3C).…”

Section: Discussionmentioning

confidence: 99%

“…Hence, inhibiting autophagy is considered to be a potentially effective strategy against MM 25 . In most cases, autophagy plays an anti‐apoptotic role by raising the stress threshold required for the induction of apoptosis, or by directly suppressing apoptosis 17,26,27 . However, in rare cases, excessive autophagy can lead to ACD of tumour cells due to the extreme degradation of the organelles and cytoplasm 28,29 .…”

Section: Discussionmentioning

confidence: 99%

Solamargine induces autophagy‐mediated apoptosis and enhances bortezomib activity in multiple myeloma

Han

Bai

et al. 2022

Clin Exp Pharma Physio

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Multiple myeloma (MM) is an incurable plasma cell malignancy with a poor survival rate. Conventional chemotherapeutic agent-induced adverse events, including toxicity, neuropathy or drug resistance, significantly decrease the patients' quality of life and can even lead to interruption of treatment. Therefore, novel therapeutic drugs and strategies are urgently needed to improve MM therapy and patient outcomes. Here, we show that solamargine (SM), a steroidal alkaloid glycoside isolated from a Chinese herb Solanum nigrum L., exhibits promising anti-MM activity. In particular, SM suppressed the viability of MM cell lines (ARP-1 and NCI-H929) in a concentrationand time-dependent manner, inducing apoptosis in these cells. RNA-seq analysis showed that treatment with SM led to the upregulation of genes associated with cell death and autophagy in H929 cells. Further, we found that treatment with SM activated autophagy in the MM cells, as incubation with 3-Methyladenine, an inhibitor of autophagy, significantly alleviated SM-triggered apoptosis and inhibition of viability in MM cells. Interestingly, we also observed a synergistic effect between SM and bortezomib (BTZ), a common chemotherapeutic agent for MM, in both MM cells and human bone marrow CD138+ primary myeloma cells. We also confirmed the singleagent efficacy of SM and the synergistic effects between SM and BTZ in an MM xenograft mouse model. Collectively, these findings indicate that SM exerts an anti-MM effect, at least in part, by activating cell autophagy and reveal that SM alone or in combination with BTZ is a potential therapeutic strategy for treating MM.

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“…The rational of phenothiazine repurposing for cancer therapy has been previously explored and TFP has shown promising anticancer effect in several cancer types ( 42 , 43 , 44 , 45 , 46 ). It was reported to suppress the invasion of metastatic cancer cell lines, by reducing angiogenesis ( 43 ), and to induce lysosome-dependent cancer cell death, through its ability to accumulate in acidic lysosomes (an ability of cationic amphiphilic compounds), thus sensitizing cancer cells to chemotherapy ( 42 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

Phenothiazines alter plasma membrane properties and sensitize cancer cells to injury by inhibiting annexin-mediated repair

Heitmann

Zanjani

Klenow

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Trifluoperazine induces cellular apoptosis by inhibiting autophagy and targeting NUPR1 in multiple myeloma

Cited by 22 publications

References 28 publications

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension

Solamargine induces autophagy‐mediated apoptosis and enhances bortezomib activity in multiple myeloma

Phenothiazines alter plasma membrane properties and sensitize cancer cells to injury by inhibiting annexin-mediated repair

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