Nelfinavir Induces Endoplasmic Reticulum Stress and Sensitizes Renal Cancer Cells to TRAIL

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

doi:10.21873/anticanres.12754

Cited by 13 publications

(19 citation statements)

References 34 publications

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“…Interestingly, we found that the combination of lopinavir and ritonavir triggered TRAIL-receptor-mediated cytotoxicity and apoptosis by increasing the expression of the TRAIL receptor DR5. Several studies have shown that ER stress induction increased the expression of TRAIL receptors, thereby sensitizing cancer cells to TRAIL and inducing TRAIL-mediated apoptosis (11,14,38). Compatible with those studies, the increased DR5 expression we found was shown to be due to ER stress induced by the combination.…”

Section: Discussionsupporting

confidence: 76%

“…Inducing ER stress is an innovative approach to cancer therapy (7). HIV protease inhibitors are known to induce ER stress (4,8,14,17,18), and in the present study we demonstrated that the lopinavir-ritonavir combination synergistically suppressed the growth of both renal cancer cells and bladder cancer cells by inducing ER stress. Because ritonavir has been shown not only to increase the amount of unfolded proteins by inhibiting molecular chaperones (4) but also to act as a chemical booster (3,4), it is thought to be an ideal drug for inducing extensive ER stress in combination with other ER-stress-inducing agents (4,(19)(20)(21).…”

Section: Discussionsupporting

confidence: 61%

“…The combination increased the expression of a TRAIL receptor and thereby sensitized cancer cells to TRAIL. ER stress induction reportedly increases the expression of TRAIL receptors (11,14,15). Therefore, we next evaluated whether the combination increases the expression of a TRAIL receptor and thereby sensitizes the cancer cells to TRAIL.…”

Section: Resultsmentioning

confidence: 99%

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Lopinavir-Ritonavir Combination Induces Endoplasmic Reticulum Stress and Kills Urological Cancer Cells

et al. 2019

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Background/Aim: Induction of endoplasmic reticulum (ER) stress is a novel approach to cancer treatment. This study investigated the ability of the clinically feasible combination of the human immunodeficiency virus protease inhibitors lopinavir and ritonavir to induce ER stress killing urological cancer cells. Materials and Methods: Renal cancer cells (769-P, 786-O) and bladder cancer cells (UMUC-3, T-24) were used to investigate the ability of the combination to induce ER stress and its mechanism of action. Results: The combination inhibited the growth of both renal and bladder cancer cells synergistically by inducing ER stress. The combination-induced ER stress increased the expression of AMP-activated protein kinase and suppressed the mammalian target of rapamycin pathway. It also increased the expression of a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor and thereby sensitized the cancer cells to TRAIL. Conclusion: The combination of lopinavir and ritonavir acts against urological cancer cells by inducing ER stress synergistically. Materials and Methods Cell culture. Human renal cancer cells (769-P, 786-O) and human bladder cancer cells (UMUC-3, T-24) were purchased from the American Type Culture Collection (Rockville, MD, USA). The cells were cultured in either Roswell Park Memorial Institute Medium 1640 (769-P and 786-O cells), Minimum Essential Medium (UMUC-3 cells), or McCoy's 5A medium (T-24 cells) containing 10% fetal bovine serum and 1.0% penicillin/streptomycin (Invitrogen, Carlsbad, CA, USA) at 37˚C under 5% CO 2 in a humidified incubator. Reagents and antibodies. Ritonavir purchased from Toronto Research Chemicals (North York, ON, Canada) and lopinavir purchased from Selleck (Houston, TX, USA) were dissolved in dimethyl sulfoxide. Cycloheximide purchased from Enzo Life Sciences (Farmingdale, NY, USA) was dissolved in distilled water. Human recombinant TRAIL purchased from R&D Systems (Minneapolis, MN, USA) was dissolved in sterile phosphatebuffered saline (PBS) containing 0.1% bovine serum albumin. These solutions were stored at −80˚C or −20˚C until use. Primary antibodies for western blotting were used against the following: survivin and death receptor 5 (DR5) (Santa Cruz Biotechnology, Santa Cruz, CA, USA); cleaved poly(ADP-ribose) polymerase (PARP), S6 ribosomal protein, phosphorylated S6, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), and 5891 This article is freely accessible online.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 61%

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Lopinavir-Ritonavir Combination Induces Endoplasmic Reticulum Stress and Kills Urological Cancer Cells

et al. 2019

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“…ER stress is induced when the amount of misfolded protein exceeds the capacity of the ER refolding capacity, and prolonged ER stress kills cancer cells [51]. We have previously reported that ER stress had multiple effects—such as HDAC inhibition [24], [52], [53], mTOR suppression [22], [54] and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor upregulation [55]—and killed urological cancer cells effectively [24], [52], [53], [54], [55], [56]. In the present study the combination of panobinostat and metformin induced ER stress cooperatively, and this would be an important mechanism of the combination's anticancer action.…”

Section: Discussionmentioning

confidence: 99%

Metformin Augments Panobinostat's Anti-Bladder Cancer Activity by Activating AMP-Activated Protein Kinase

Okubo

Isono

Asano

et al. 2019

Translational Oncology

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Panobinostat, a histone deacetylase inhibitor, induces histone acetylation and acts against cancer but attenuates its anticancer activity by activating the mammalian target of rapamycin (mTOR) pathway. AMP-activated protein kinase (AMPK) is a cellular energy sensor that reportedly inhibits the mTOR pathway. The antidiabetic drug metformin is also a potent AMPK activator and we investigated whether it augmented panobinostat's antineoplastic activity in bladder cancer cells (UMUC3, J82, T24 and MBT-2). Metformin enhanced panobinostat-induced apoptosis and the combination inhibited the growth of bladder cancer cells cooperatively in vitro and in vivo . As expected, metformin increased the phosphorylation of AMPK and decreased the panobinostat-caused phosphorylation of S6 ribosomal protein, thus inhibiting the panobinostat-activated mTOR pathway. The AMPK activation was shown to play a pivotal role in the combination's action because the AMPK inhibitor compound C attenuated the combination's anticancer activity. Furthermore, the AMPK activation by metformin enhanced panobinostat-induced histone and non-histone acetylation. This acetylation was especially remarkable in the proteins in the detergent-insoluble fraction, which would be expected if the combination also induced endoplasmic reticulum stress.

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“…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%

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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Nelfinavir Induces Endoplasmic Reticulum Stress and Sensitizes Renal Cancer Cells to TRAIL

Abstract: Nelfinavir induces ER stress in renal cancer cells and sensitizes them to TRAIL.

Cited by 13 publications

References 34 publications

Lopinavir-Ritonavir Combination Induces Endoplasmic Reticulum Stress and Kills Urological Cancer Cells

Lopinavir-Ritonavir Combination Induces Endoplasmic Reticulum Stress and Kills Urological Cancer Cells

Metformin Augments Panobinostat's Anti-Bladder Cancer Activity by Activating AMP-Activated Protein Kinase

Simvastatin-Romidepsin Combination Kills Bladder Cancer Cells Synergistically

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