Ritonavir-Mediated Induction of Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways

Batchu, Ramesh B.; Gruzdyn, Oksana V.; Bryant, Christopher S.; Qazi, Aamer; Kumar, Sanjeev; Chamala, Sreedhar; Kung, Shu Ting; Sanka, Ramana S.; Puttagunta, Udaya Sri; Weaver, Donald W.; Gruber, Scott A.

doi:10.3390/ph7010046

Cited by 38 publications

(39 citation statements)

References 19 publications

(20 reference statements)

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“…For pancreatic cancer, ritonavir, an HIV inhibitor, was identified as an antitumor agent inhibiting cell cycle progression (Batchu et al ., 2014). Recently, bazedoxifene, which is approved as an estrogen modulator, was revealed as an anti‐GP130 signaling agent that can inhibit pancreatic cancer cell growth (Wu et al ., 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Drug-repositioning screening has been increasingly performed to identify therapeutic agents for complex diseases (Li and Jones, 2012) because of the high cost and long time required for the development of novel therapeutic agents. For pancreatic cancer, ritonavir, an HIV inhibitor, was identified as an antitumor agent inhibiting cell cycle progression (Batchu et al, 2014). Recently, bazedoxifene, which is approved as an estrogen modulator, was revealed as an anti-GP130 signaling agent that can inhibit pancreatic cancer cell growth (Wu et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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A drug‐repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6‐thioguanine as an effective therapeutic agent for TPMT‐low cancer cells

et al. 2018

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Pancreatic cancer is one of the most difficult cancers to cure due to the lack of early diagnostic tools and effective therapeutic agents. In this study, we aimed to isolate new bioactive compounds that effectively kill pancreatic ductal adenocarcinoma (PDAC) cells, but not untransformed, human pancreatic ductal epithelial (HPDE) cells. To this end, we established four primary PDAC cell lines and screened 4141 compounds from four bioactive‐compound libraries. Initial screening yielded 113 primary hit compounds that caused over a 50% viability reduction in all tested PDAC cells. Subsequent triplicate, dose‐dependent analysis revealed three compounds with a tumor cell‐specific cytotoxic effect. We found that these three compounds fall into a single category of thiopurine biogenesis. Among them, 6‐thioguanine (6‐TG) showed an IC50 of 0.39–1.13 μm toward PDAC cells but had no effect on HPDE cells. We propose that this cancer selectivity is due to differences in thiopurine methyltransferase (TPMT) expression between normal and cancer cells. This enzyme is responsible for methylation of thiopurine, which reduces its cytotoxicity. We found that TPMT levels were lower in all four PDAC cell lines than in HPDE or Panc1 cells, and that knockdown of TPMT in HPDE or Panc1 cells sensitized them to 6‐TG. Lastly, we used a patient‐derived xenograft model to confirm that 6‐TG has a significant antitumor effect in combination with gemcitabine. Overall, our study presents 6‐TG as a strong candidate for use as a therapeutic agent against PDAC with low levels of TPMT.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A drug‐repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6‐thioguanine as an effective therapeutic agent for TPMT‐low cancer cells

et al. 2018

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“…Ritonavir in vitro exposure increased apoptosis and decreased proliferation of pancreatic ductal adenocarcinoma cell lines which led the authors to conclude that using ritonavir in pancreatic duct cell cancer by “drug repositioning…would limit the costs and reduce risks” [212]. Our point exactly times nine.…”

Section: Introductionmentioning

confidence: 99%

“…Decreased AKT phosphorylation is a basic mode of action in ritonavir cytotoxicity [212, 217, 219]. Again the refrain, “[ritonavir] repositioning for ovarian cancer… would reduce risks, limit the costs and decrease the time needed to bring the drug from bench to bedside” [219].…”

Section: Introductionmentioning

confidence: 99%

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

Kast¹,

2014

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CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs- aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

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“…Ritonavir is used for the treatment of viral infections, such as infection with hepatitis C virus and HIV‐1 . Moreover, ritonavir has been shown to trigger apoptosis and is considered for the treatment of malignancy . On the other hand, ritonavir has been shown to protect against oxidative stress‐induced apoptosis of hippocampal neurons and peripheral blood mononuclear cells.…”

mentioning

confidence: 99%

Ritonavir‐Induced Suicidal Death of Human Erythrocytes

Waibel

Bissinger

Bouguerra

et al. 2016

Basic Clin Pharma Tox

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The antiviral drug ritonavir has been shown to trigger suicidal death or apoptosis of tumour cells and has thus been considered for the treatment of malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca 2+ entry with increase in cytosolic Ca 2+ activity ([Ca 2+ ] i ), oxidative stress and ceramide. The present study explored whether and how ritonavir induces eryptosis. To this end, flow cytometry was employed to estimate cell volume from forward scatter, phosphatidylserine exposure at the cell surface from Annexin-V binding, [Ca 2+ ] i from Fluo3 fluorescence, abundance of reactive oxygen species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence and ceramide abundance utilizing specific antibodies. As a result, a 48-hr exposure of human erythrocytes to ritonavir significantly increased the percentage of Annexin-V-binding cells (≥5 lg/ml), significantly decreased forward scatter (≥5 lg/ml), significantly increased Fluo3 fluorescence (20 lg/ml), slightly, but significantly increased DCFDA fluorescence (20 lg/ml) and slightly, but significantly increased ceramide abundance (20 lg/ml). The effect of ritonavir on Annexin-V binding was significantly blunted, but not fully abolished by the removal of extracellular Ca 2+ . In conclusion, ritonavir triggers erythrocyte shrinkage and phosphatidylserine translocation at the erythrocyte cell membrane, an effect in part due to the stimulation of Ca 2+ entry, oxidative stress and ceramide. Ritonavir is used for the treatment of viral infections, such as infection with hepatitis C virus [1-3] and HIV-1 [4-10].Moreover, ritonavir has been shown to trigger apoptosis [11][12][13][14][15][16][17][18][19][20] and is considered for the treatment of malignancy [10,11,14,19,20]. On the other hand, ritonavir has been shown to protect against oxidative stress-induced apoptosis of hippocampal neurons and peripheral blood mononuclear cells. Ritonavir is effective by modifying the activity of diverse cellular mechanisms including cytochrome P450 [1,8,10,21,22 [24,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], and enhanced eryptosis is observed in diverse clinical conditions, such as chronic kidney disease (CKD), haemolytic uraemic syndrome, dehydration, hyperphosphataemia, diabetes, hepatic failure, malignancy, sepsis, fever, sickle cell disease, beta-thalassaemia, Hb-C and G6PD deficiency, as well as Wilson's disease [24]. The present study explored whether and how ritonavir triggers eryptosis. To this end, human erythrocytes from healthy volunteers were treated with ritonavir, and phosphatidylserine surface abundance, cell volume, [Ca 2+ ] i , reactive oxygen species (ROS) and ceramide abundance were determined by flow cytometry. Materials and MethodsErythrocytes, solutions and chemicals. Fresh Li-heparin-anti...

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Ritonavir-Mediated Induction of Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways

Cited by 38 publications

References 19 publications

A drug‐repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6‐thioguanine as an effective therapeutic agent for TPMT‐low cancer cells

A drug‐repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6‐thioguanine as an effective therapeutic agent for TPMT‐low cancer cells

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

Ritonavir‐Induced Suicidal Death of Human Erythrocytes

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