Identification of nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer

Rashid, Narmeen S; Hairr, Nicole S.; Murray, Graeme; Olex, Amy L.; Leftwich, Tess J.; Grible, Jacqueline M; Reed, Jason; Dozmorov, Mikhail G.; Harrell, J. Chuck

doi:10.1016/j.tranon.2021.101235

Cited by 10 publications

(12 citation statements)

References 45 publications

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“…Overexpression of Exportin-1 (XPO1) has been observed in breast cancer as compared to normal tissues in the vicinity . p53, a tumor suppressor, has been discovered to have an antitumor effect that is closely linked to its retention in the nucleus and this effect can be either direct or indirect, through the promotion of apoptosis. , In order to verify the inhibitory effect of KPT on nuclear function, the cellular XPO1 protein and p53 protein level were measured by Western blotting experiments (Figure A).…”

Section: Resultsmentioning

confidence: 99%

Enhance Mitochondrial Damage by Nuclear Export Inhibition to Suppress Tumor Growth and Metastasis with Increased Antitumor Properties of Macrophages

Yao

Tao

Lyu

et al. 2023

ACS Appl. Mater. Interfaces

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Mitochondria-targeting damage has become a popular therapeutic option for tumor metastasis; however, its efficacy is limited by the adaptive rescue capacity of nuclei. There is an urgent need for a dual mitochondrial and nuclear targeting strategy that can also increase the antitumor capacity of macrophages. In this study, XPO1 inhibitor KPT-330 nanoparticles were combined with mitochondria-targeting lonidamine (TPP-LND) nanoparticles. The combination of nanoparticles with a 1:4 ratio of KPT and TL demonstrated the best synergistic effect in restraining the proliferation and metastasis of 4T1 breast cancer cells. Investigating the mechanisms both in vitro and in vivo, it was found that KPT nanoparticles not only directly impede tumor growth and metastasis by controlling the expression of associated proteins but also indirectly facilitate mitochondrial damage. The two nanoparticles synergistically decreased the expression of cytoprotective factors, such as Mcl-1 and Survivin, causing mitochondrial dysfunction and thus inducing apoptosis. Additionally, it downregulated metastasis-related proteins like HIF-1α, vascular endothelial growth factor (VEGF), and matrix metalloproteinase 2 (MMP-2) and reduced endothelial-to-mesenchymal transition. Significantly, their combination increased the ratio of M1 tumor-associated macrophages (TAMs)/M2 TAMs both in vitro and in vivo and increased the phagocytosis of tumor cells by macrophages, thus suppressing tumor growth and metastasis. In summary, this research revealed that nuclear export inhibition can synergistically enhance the prevention of mitochondrial damage to tumor cells, heightening the antitumor properties of TAMs, thereby providing a viable and safe therapeutic approach for the treatment of tumor metastasis.

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Section: Resultsmentioning

confidence: 99%

Enhance Mitochondrial Damage by Nuclear Export Inhibition to Suppress Tumor Growth and Metastasis with Increased Antitumor Properties of Macrophages

Yao

Tao

Lyu

et al. 2023

ACS Appl. Mater. Interfaces

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“…Human breast cancer cell lines were grown under standard tissue culture conditions and miRNAs harvested from lines in log-phase growth. PDXs were grown in Nod Scid Gamma mice and the tumors were removed when in log-phase growth (∼8 mm across). , MiRNAs were purified from both sources with a Qiagen miRNeasy Tissue/Cells Advanced Kit using the manufacturers recommended protocol.…”

Section: Methodsmentioning

confidence: 99%

“…PDXs were grown in Nod Scid Gamma mice and the tumors were removed when in log-phase growth (∼8 mm across). 75,76 MiRNAs were purified from both sources with a Qiagen miRNeasy Tissue/Cells Advanced Kit using the manufacturers recommended protocol.…”

Section: ■ Conclusionmentioning

confidence: 99%

Single-Molecule Sensor for High-Confidence Detection of miRNA

et al. 2022

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MicroRNAs (miRNAs) play a crucial role in regulating gene expression and have been linked to many diseases. Therefore, sensitive and accurate detection of disease-linked miRNAs is vital to the emerging revolution in early diagnosis of diseases. While the detection of miRNAs is a challenge due to their intrinsic properties such as small size, high sequence similarity among miRNAs and low abundance in biological fluids, the majority of miRNA-detection strategies involve either target/signal amplification or involve complex sensing designs. In this study, we have developed and tested a DNA-based fluorescence resonance energy transfer (FRET) sensor that enables ultrasensitive detection of a miRNA biomarker (miRNA-342-3p) expressed by triple-negative breast cancer (TNBC) cells. The sensor shows a relatively low FRET state in the absence of a target but it undergoes continuous FRET transitions between low- and high-FRET states in the presence of the target. The sensor is highly specific, has a detection limit down to low femtomolar (fM) without having to amplify the target, and has a large dynamic range (3 orders of magnitude) extending to 300 000 fM. Using this strategy, we demonstrated that the sensor allows detection of miRNA-342-3p in the miRNA-extracts from cancer cell lines and TNBC patient-derived xenografts. Given the simple-to-design hybridization-based detection, the sensing platform developed here can be used to detect a wide range of miRNAs enabling early diagnosis and screening of other genetic disorders.

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“…In vitro 178,313 Bcl-xL/Bcl-2 inhibitor in vitro and vivo 320 ; Irradiation in vitro and in vivo 186 ; olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor in vitro and vivo 321 Lung cancer Both Enzalutamide in vivo 322 ; cisplatin in vitro and vivo 190,322 ; irinotecan in vitro and vivo 190 ; KRAS G12C inhibitor in vitro and vivo 191 ; PARP1 inhibition in vitro and vivo 189 ; Bcl-xL inhibitor in vitro and vivo 184 Breast cancer Both 95,312 Tamoxifen in vitro and vivo 134 ; olaparib, a PARP inhibitor in vitro and vivo 199 ; LOM612, a small molecule activator of FOXO nuclear-cytoplasmic shuttling in vitro and in vivo 323 ; a PI3K/mTOR inhibitor in vitro and in vivo 197 ; tucidinostat in vitro and vivo 201 ; Y219, a novel proteasome inhibitor in vitro and vivo 324 (Continues)…”

Section: Gastric Cancermentioning

confidence: 99%

The nuclear export protein exportin‐1 in solid malignant tumours: From biology to clinical trials

Lai,

Xu,

Dai

2024

Clinical & Translational Med

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BackgroundExportin‐1 (XPO1), a crucial protein regulating nuclear‐cytoplasmic transport, is frequently overexpressed in various cancers, driving tumor progression and drug resistance. This makes XPO1 an attractive therapeutic target. Over the past few decades, the number of available nuclear export‐selective inhibitors has been increasing. Only KPT‐330 (selinexor) has been successfully used for treating haematological malignancies, and KPT‐8602 (eltanexor) has been used for treating haematologic tumours in clinical trials. However, the use of nuclear export‐selective inhibitors for the inhibition of XPO1 expression has yet to be thoroughly investigated in clinical studies and therapeutic outcomes for solid tumours.MethodsWe collected numerous literatures to explain the efficacy of XPO1 Inhibitors in preclinical and clinical studies of a wide range of solid tumours.ResultsIn this review, we focus on the nuclear export function of XPO1 and results from clinical trials of its inhibitors in solid malignant tumours. We summarized the mechanism of action and therapeutic potential of XPO1 inhibitors, as well as adverse effects and response biomarkers.ConclusionXPO1 inhibition has emerged as a promising therapeutic strategy in the fight against cancer, offering a novel approach to targeting tumorigenic processes and overcoming drug resistance. SINE compounds have demonstrated efficacy in a wide range of solid tumours, and ongoing research is focused on optimizing their use, identifying response biomarkers, and developing effective combination therapies.Key Points Exportin‐1 (XPO1) plays a critical role in mediating nucleocytoplasmic transport and cell cycle. XPO1 dysfunction promotes tumourigenesis and drug resistance within solid tumours. The therapeutic potential and ongoing researches on XPO1 inhibitors in the treatment of solid tumours. Additional researches are essential to address safety concerns and identify biomarkers for predicting patient response to XPO1 inhibitors.

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Identification of nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer

Cited by 10 publications

References 45 publications

Enhance Mitochondrial Damage by Nuclear Export Inhibition to Suppress Tumor Growth and Metastasis with Increased Antitumor Properties of Macrophages

Enhance Mitochondrial Damage by Nuclear Export Inhibition to Suppress Tumor Growth and Metastasis with Increased Antitumor Properties of Macrophages

Single-Molecule Sensor for High-Confidence Detection of miRNA

The nuclear export protein exportin‐1 in solid malignant tumours: From biology to clinical trials

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