Nelfinavir and Ritonavir Kill Bladder Cancer Cells Synergistically by Inducing Endoplasmic Reticulum Stress

Sato, Akinori; Okubo, Kazuki; Isono, Motohide; Asano, Tomohiko

doi:10.3727/096504017x14957929842972

Cited by 19 publications

(30 citation statements)

References 36 publications

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“…In the present study, inhibition of ER stress by cycloheximide markedly impaired the combination's ability to cause histone acetylation and induce apoptosis, suggesting that the ER stress induction played a pivotal role in the combination's action. This ER stress-histone acetylation sequence is also consistent with our previous results that there is a crosstalk between histone acetylation and ER stress induction [29,30,73,74,80]. The decreased expression of HDACs is thought to be a consequence of the ER stress induction according to the previous studies [29,30,73,74,80].…”

Section: Discussionsupporting

confidence: 91%

“…This ER stress-histone acetylation sequence is also consistent with our previous results that there is a crosstalk between histone acetylation and ER stress induction [29,30,73,74,80]. The decreased expression of HDACs is thought to be a consequence of the ER stress induction according to the previous studies [29,30,73,74,80]. This HDAC suppression might further enhance the histone acetylation and even the ER stress because HDAC suppression abrogates molecular chaperone function, causing the accumulation of unfolded proteins [70][71][72].…”

Section: Discussionsupporting

confidence: 90%

“…Unexpectedly, the simvastatin-induced AMPK activation was further promoted by romidepsin, which might also play a role in enhancing the histone acetylation. This AMPK activation was thought to be due to ER stress induction by the combination because the ER stressor tunicamycin increased the expression of AMPK, which is consistent with the previous reports [29,30,73,74]. ER stress is caused by the accumulation and aggregation of unfolded proteins [75], and excessive ER stress causes apoptosis and kills cancer cells [76][77][78].…”

Section: Discussionsupporting

confidence: 89%

“…ER stress is caused by the accumulation and aggregation of unfolded proteins [75], and excessive ER stress causes apoptosis and kills cancer cells [76][77][78]. We have demonstrated that ER stress-inducing drugs or drug combinations killed urological cancers effectively [73,74,79,80] and, in fact, tunicamycin actually inhibited bladder cancer growth in a dose-dependent fashion. In the present study, inhibition of ER stress by cycloheximide markedly impaired the combination's ability to cause histone acetylation and induce apoptosis, suggesting that the ER stress induction played a pivotal role in the combination's action.…”

Section: Discussionmentioning

confidence: 99%

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Simvastatin-Romidepsin Combination Kills Bladder Cancer Cells Synergistically

Okubo

Miyai

Kato

et al. 2020

Preprint

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Abstract Background The HMG-CoA reductase inhibitor simvastatin activates AMP-activated protein kinase (AMPK) and thereby induces histone acetylation. We postulated that combining simvastatin with the histone deacetylase (HDAC) inhibitor romidepsin would kill bladder cancer cells by inducing histone acetylation cooperatively. Methods Bladder cancer cells (UMUC-3, T-24, J-82, MBT-2) were treated with simvastatin and romidepsin. Cell viability and clonogenicity were assessed by CCK-8 assay and colony formation assay. In-vivo efficacy was evaluated using murine subcutaneous tumor models. Flow cytometry was used to detect annexin-V positive cells and to evaluate cell cycle distribution and cellular reactive oxygen species (ROS) production. Induction of histone acetylation and the expression of AMPK, HDACs, peroxisome proliferator-activated receptor (PPAR) γ, cell-cycle regulators, and the endoplasmic reticulum (ER) stress markers were evaluated by western blotting. Results The combination of romidepsin and simvastatin induced robust apoptosis and killed bladder cancer cells synergistically (combination indexes < 1). It also suppressed colony formation significantly. In murine subcutaneous tumor models using MBT-2 cells, a 15-day treatment with 0.5 mg/kg romidepsin and 15 mg/kg simvastatin was well tolerated and inhibited tumor growth significantly. Mechanistically, the combination induced histone acetylation by activating AMPK. The combination also decreased the expression of HDACs, thus further promoting histone acetylation. This AMPK activation was essential for the combination’s action because compound C, an AMPK inhibitor, suppressed the combination-induced histone acetylation and the combination’s ability to induce apoptosis. We also found that the combination increased the expression of PPARγ, leading to ROS production. Furthermore, the combination induced ER stress and this ER stress was shown to be associated with increased AMPK expression and histone acetylation, thus playing an important role in the combination’s action. Our study also suggests there is a positive feedback cycle between ER stress induction and PPARγ expression. Conclusions The combination of simvastatin and romidepsin kills bladder cancer cells synergistically. Its mechanism of action includes ER stress induction, AMPK activation, histone acetylation, and increased PPARγ expression. Background There is currently no curative treatment for metastatic bladder cancer and development of novel treatment strategy is urgently needed. AMP-activated protein kinase (AMPK) is a cellular energy sensor, which is activated by impaired energy status such as glucose deprivation, ischemia, hypoxia, and oxidative stress, leading to inhibition of cellular growth to restore energy homeostasis [1]. Therefore, drugs activating AMPK have attracted much attention as novel anticancer agents [2–5]. HMG-CoA reductase inhibitors, which are widely used for treating dyslipidemia [6–9], are known to activate AMPK [10–12]. Simvastatin inhibits HMG-CoA reductase and has been shown to kill cancer cells in vitro [12–14], although its anticancer efficacy has not been proven yet in clinical trials [15].

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Simvastatin-Romidepsin Combination Kills Bladder Cancer Cells Synergistically

Okubo

Miyai

Kato

et al. 2020

Preprint

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“…[4][5][6][7][8] NFV has also been shown to have in vitro efficacy against a wide range of malignancies by causing apoptosis and nonapoptotic cell death and is under clinical investigation as a cancer therapeutic agent in humans. [9][10][11] Pregnant women living with HIV receive antiretrovirals for their own health and to prevent HIV transmission to their infants. 6 Physiologic changes associated with pregnancy may have a large impact on drug disposition, with effects on drug absorption, distribution, metabolism, and elimination of antiretrovirals.…”

mentioning

confidence: 99%

Pharmacokinetics of Increased Nelfinavir Plasma Concentrations in Women During Pregnancy and Postpartum

Eke

McCormack

Best

et al. 2018

The Journal of Clinical Pharma

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This study aims to evaluate the safety, acceptability, and pharmacokinetics (PK) of an increased dose of nelfinavir (NFV) during the third trimester of pregnancy. The study was registered as part of the International Maternal Pediatric Adolescent AIDS Clinical Trials network (IMPAACT-P1026s), an ongoing multicenter prospective cohort study of antiretroviral PK during pregnancy (NCT00042289). NFV intensive PK evaluations were performed at steady state during the third trimester of pregnancy and 2-3 weeks postpartum. Plasma concentrations of NFV and its active metabolite, hydroxyltert-butylamide (M8) were measured using high-performance liquid chromatography with ultraviolet detection. A total of 18 women are included in the analysis. NFV area under the concentration-time curve (AUC) with the increased dose during the third trimester was nearly identical to the standard dose postpartum, with a geometric mean ratio for third trimester to postpartum AUC of 0.98 (90%CI 0.71-1.35). Despite the increased dose, M8 AUC was lower during the third trimester compared to postpartum (0.53, IQR [0.38-0.75]), as was the M8/NFV AUC ratio (0.51, IQR [0.42-0.63]). NFV AUC 0-12 was above target in 15 of 18 (83%) of participants during the third trimester compared to 14 of 16 (88%) postpartum. No major safety concerns were noted. Increasing the NFV dose to 1875 mg twice daily during the third trimester achieved similar concentrations postpartum compared to standard dosing (1250 mg twice daily). Increased NFV dose regimens may still have some benefit to human immunodeficiency virus (HIV)-positive pregnant women living in countries where novel protease inhibitors are currently unavailable or in individuals who are intolerant to ritonavir-boosted HIV medications.

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