Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms

Kim, Ji Yeong; Son, Ji Yeon; Lee, Byung‐Mu; Kim, Hyung Sik; Yoon, Sungpil

doi:10.21873/anticanres.12837

Cited by 16 publications

(32 citation statements)

References 16 publications

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“…Eribulin is a recently developed promising antimitotic drug for the treatment of resistant cancers (43)(44)(45). We found that P-gp-overexpressing KBV20C cells were highly resistant to eribulin compared with drug-sensitive KB cells (14,36,37), and we assumed that crizotinib could be a useful drug against eribulin-resistant cancer cells, which arise from eribulin chemotherapy.…”

Section: Discussionmentioning

confidence: 92%

“…Annexin V analysis was conducted by using the annexin Vfluorescein isothiocyanate (FITC) staining kit (BD Bioscience, Franklin, NJ, USA) as previously described (13,(33)(34)(35)(36)(37). Cells were grown in 60-mm diameter dishes and treated with the indicated drugs for 24 h. The cells were then dislodged by trypsin and pelleted by centrifugation.…”

Section: Annexin V Analysismentioning

confidence: 99%

“…Next, we compared the sensitizing effect of crizotinib on drugresistant KBV20C cells and drug-sensitive parent KB cells, as low-dose crizotinib is able to specifically sensitize P-gpoverexpressing drug-resistant KBV20C cells while not affecting drug-sensitive parent KB cells. We previously reported that P-gp-overexpressing KBV20C cells were highly resistant to antimitotic drugs, such as eribulin (12,36,37). Eribulin was recently developed and is a promising drug for the treatment of drug-resistant cancer (43)(44)(45).…”

Section: Low-dose Crizotinib Specifically Sensitizes Drug-resistant Kmentioning

confidence: 99%

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Low-Dose Crizotinib, a Tyrosine Kinase Inhibitor, Highly and Specifically Sensitizes P-Glycoprotein-Overexpressing Chemoresistant Cancer Cells Through Induction of Late Apoptosis in vivo and in vitro

et al. 2020

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We investigated possible conditions or drugs that could target P-glycoprotein (P-gp)-overexpressing drug-resistant KBV20C cancer cells. Specifically, we focused on identifying a single treatment with a relatively low half maximal inhibitory concentration (IC 50). Our approach utilized repurposing drugs, which are already used in clinical practice. We evaluated 13 TKIs (gefitinib, imatinib, erlotinib, nilotinib, pazopanib, masatinib, sunitinib, sorafenib, regorafenib, lapatinib, vandetanib, cediranib, and crizotinib) for their sensitizing effects on P-gp-overexpressing drug-resistant KBV20C cells. We found that crizotinib had a much greater sensitization effect than the other tested drugs at relatively low doses. In a detailed quantitative analysis using both lower doses and time-duration treatments, we demonstrated that crizotinib, which increased the levels of apoptosis and G2 arrest, was the best TKI to induce sensitization in P-gp-overexpressing KBV20C cells. Upon comparing resistant KBV20C cells and sensitive KB parent cells, crizotinib was found to markedly sensitize drug-resistant KBV20C cancer cells compared with other TKIs. This suggests that crizotinib is a resistant cancer cell-sensitizing drug that induces apoptosis. In mice bearing xenografted P-gp-overexpressing KBV20C cells, we confirmed that crizotinib significantly reduced tumor growth and weight, without apparent side effects. In addition, although lapatinib and crizotinib have a high P-gp inhibitory activity, we found that co-treatment with crizotinib and vincristine (VIC) did not have much of a sensitization effect on KBV20C cells, whereas lapatinib had a high sensitization effect on VIC-treated KBV20C cells. This suggests that crizotinib is a single-treatment specific drug for resistant cancer cells. These findings provide valuable information regarding the sensitization of drug-resistant cells and indicate that low-dose crizotinib monotherapy may be used in patients with specific P-gp-overexpressing chemoresistant cancer.

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Section: Discussionmentioning

confidence: 92%

Section: Annexin V Analysismentioning

confidence: 99%

Section: Low-dose Crizotinib Specifically Sensitizes Drug-resistant Kmentioning

confidence: 99%

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Low-Dose Crizotinib, a Tyrosine Kinase Inhibitor, Highly and Specifically Sensitizes P-Glycoprotein-Overexpressing Chemoresistant Cancer Cells Through Induction of Late Apoptosis in vivo and in vitro

et al. 2020

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“…8.4 . The whole arise of the drug repositioning integration started with blinded serendipity–based repositioning stories, such as sildenafil, minoxidil, and everolimus [ 75 , 76 ]. Consequently, the strategic progress led to disease network–based repositioning where certain diseases share same histological, pathological, pharmacological, or biochemical phenotypes; this certainly could be potential opportunity for testing the already established drugs for identified diseases to be evaluated for other different diseases having the same histopathological/biochemical features.…”

Section: Drug Repositioning Strategies Developmentmentioning

confidence: 99%

Successful stories of drug repurposing for cancer therapy in hepatocellular carcinoma

Attia

Ewida

Ahmed

2020

Drug Repurposing in Cancer Therapy

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“…Drug repurposing and the development of its derivatives have emerged as an attractive strategy in combating malignant tumors. Phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil and vardenafil) either mono-treatment or combination with cancer therapeutic drugs have been suggested to display anti-proliferative and apoptotic activities in vitro and suppress tumor growth in vivo against several cancers, such as prostate cancer, lung cancer, breast cancer, colon adenocarcinoma, neuroblastoma, and oral cancer [5][6][7][8][9]. The inhibition of PDE5-dependent signaling has been claimed in decreasing cell migration and sensitizing apoptotic capability of anticancer medications through multiple pathways including an increase of reactive oxygen species (ROS) production, increased CD95-mediated apoptosis, enhanced endocytosis-mediated drug uptake and reduced CXCL16 expression and secretion [5,10,11].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death against Human Non-Small Cell Lung Cancers

Chang

Tseng

Leu

et al. 2020

IJMS

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Non-small cell lung cancer (NSCLC) accounts about 80% of all lung cancers. More than two-thirds of NSCLC patients have inoperable, locally advanced or metastatic tumors. Non-toxic agents that synergistically potentiate cancer-killing activities of chemotherapeutic drugs are in high demand. YL-9 was a novel and non-cytotoxic compound with the structure related to sildenafil but showing much less activity against phosphodiesterase type 5 (PDE5). NCI-H460, an NSCLC cell line with low PDE5 expression, was used as the cell model. YL-9 synergistically potentiated vinorelbine-induced anti-proliferative and apoptotic effects in NCI-H460 cells. Vinorelbine induced tubulin acetylation and Bub1-related kinase (BUBR1) phosphorylation, a necessary component in spindle assembly checkpoint. These effects, as well as BUBR1 cleavage, were substantially enhanced in co-treatment with YL-9. Several mitotic arrest signals were enhanced under combinatory treatment of vinorelbine and YL-9, including an increase of mitotic spindle abnormalities, increased cyclin B1 expression, B-cell lymphoma 2 (Bcl-2) phosphorylation and increased phosphoproteins. Moreover, YL-9 also displayed synergistic activity in combining with vinorelbine to induce apoptosis in A549 cells which express PDE5. In conclusion. the data suggest that YL-9 is a novel agent that synergistically amplifies vinorelbine-induced NSCLC apoptosis through activation of spindle assembly checkpoint and increased mitotic arrest of the cell cycle. YL-9 shows the potential for further development in combinatory treatment against NSCLC.

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Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms

Abstract: These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.

Cited by 16 publications

References 16 publications

Low-Dose Crizotinib, a Tyrosine Kinase Inhibitor, Highly and Specifically Sensitizes P-Glycoprotein-Overexpressing Chemoresistant Cancer Cells Through Induction of Late Apoptosis in vivo and in vitro

Low-Dose Crizotinib, a Tyrosine Kinase Inhibitor, Highly and Specifically Sensitizes P-Glycoprotein-Overexpressing Chemoresistant Cancer Cells Through Induction of Late Apoptosis in vivo and in vitro

Successful stories of drug repurposing for cancer therapy in hepatocellular carcinoma

Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death against Human Non-Small Cell Lung Cancers

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