Gemcitabine response in pancreatic adenocarcinoma cells is synergistically enhanced by dithiocarbamate derivatives

Pozza, Elisa Dalla; Donadelli, Massimo; Costamagna, Costanzo; Zaniboni, Tatyana; Dando, Ilaria; Franchini, Marta; Berlier, Gloria; Scarpa, Aldo; Palmieri, Marta

doi:10.1016/j.freeradbiomed.2011.01.001

Cited by 27 publications

(12 citation statements)

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“…Mitochondrial superoxide anions and mitochondrial membrane potential were measured by using live‐cell permeative and mitochondrial selective MitoSOX red probe and JC‐1 dye, respectively as described previously . Briefly, 3 × 10 4 cells/well were plated in black 96‐well plates and after 36 h cells were treated with 50 μM B2G2.…”

Section: Methodsmentioning

confidence: 99%

Procyanidin B2 3,3″‐di‐O‐gallate induces oxidative stress‐mediated cell death in prostate cancer cells via inhibiting MAP kinase phosphatase activity and activating ERK1/2 and AMPK

Kumar

Deep

Wempe

et al. 2017

Molecular Carcinogenesis

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Neoplastic cells exhibit higher oxidative stress compared to normal cells; however, antioxidants based clinical trials have mostly failed. Another attractive therapeutic approach is to further increase the oxidative stress in cancer cells leading to cell death.Herein, we show that Procyanidin B2 3,3″-di-O-gallate (B2G2), the most active constituent of grape seed extract, treatment causes cell death in human prostate cancer (PCa) cells (LNCaP and 22Rv1) via increasing the reactive oxygen species (ROS) generation. Mechanistically, B2G2 treatment decreased the mitochondrial electron transport chain complex III activity leading to enhanced mitochondrial superoxide generation and decreased ATP production in LNCaP cells. Additional molecular studies revealed that B2G2-induced cell death was mediated mainly through ROS-induced sustained activation of ERK1/2, which was due to inhibition of MAP kinase phosphatase (MKP) activity as over-expression of MKP3 in LNCaP cells conferred significant protection against B2G2-induced cell death. Along with ERK1/2, AMPactivated protein kinase α (AMPKα) was also activated by B2G2 treatment, and pretreatment with AMPKα inhibitor compound C significantly reversed the cytotoxic effects of B2G2 in LNCaP cells. Furthermore, pre-treatment of MKP3 over-expressing LNCaP cells with compound C further reduced the B2G2-induced cell death, suggesting the involvement of AMPKα along with MKP3 and ERK1/2 in the biological effects of B2G2. Together, these results for the first time identified that oxidative stress and MKP3 inhibition play a critical role in B2G2-induced cell death in PCa cells through sustained activation of both ERK1/2 and AMPKα. These results offer a unique opportunity to control this deadly malignancy through B2G2 use.AMP-activated kinase, dual-specificity phosphoprotein phosphatase, extracellular-signalregulated kinase, oxidative stress, procyanidin B2 3,3″-di-O-gallate, prostate cancer Abbreviations: ADT, androgen deprivation therapy; AMPKα, adenosine monophosphate-activated protein kinase alpha; ANOVA, analysis of variance; ATP, adenosine triphosphate; B2G2, procyanidin B2 3,3″-di-O-gallate; CRPC, castration-resistant prostate cancer; DCFDA, 2′,7′-dichlorofluorescein diacetate; ERK1/2, extracellular signal-regulated kinase 1/2; GSE, grape seed extract; MKP, MAP kinase phosphatase; NAC, N-acetyl-L-cysteine; PCa, prostate cancer; ROS, reactive oxygen species; SEM, standard error of mean. ROS, generated inside the cells as by-product of normal metabolism, could cause tissue injury and DNA damage but in normal cells, a dynamic balance is maintained between ROS level (pro-oxidant) and antioxidant proteins and enzymes. However, with the age this balance shifts toward pro-oxidant resulting in a chronic increase in ROS. 7-9Based upon these observations, in the past, several studies have focused on using anti-oxidants for both preventive and therapeutic approaches in the management of PCa. however, these clinical trials failed to establish any relationship between overall PCa risk and d...

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Section: Methodsmentioning

confidence: 99%

Procyanidin B2 3,3″‐di‐O‐gallate induces oxidative stress‐mediated cell death in prostate cancer cells via inhibiting MAP kinase phosphatase activity and activating ERK1/2 and AMPK

Kumar

Deep

Wempe

et al. 2017

Molecular Carcinogenesis

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“…Disulfiram has previously been documented to potentiate the effect of several chemotherapy agents in vitro: cisplatin [128], gemcitabine [101, 129] temozolomide [130], paclitaxel [100], docetaxel [131], cyclophosphamide [132], 5-fluorouracil [101, 102], doxorubicin [99], sunitinib [104], and BCNU [133]. Currently, disulfiram is in Phase I clinical trials in metastatic melanoma, in hormone refractory cancers with lung and liver metastases (, identifiers NCT00256230 and NCT00742911) as well as in prostate cancer (identifier: NCT01118741).…”

Section: Rationalementioning

confidence: 99%

A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

Kast¹,

Boockvar

Brüning³

et al. 2013

Oncotarget

151

147

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To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.

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“…Although the precise mechanism underlying the anticancer activity of this agent has not been fully elucidated, several significant clues have emerged [20-26]. Recently, Dalla Pozza et al reported that the combined treatment with gemcitabine and disulfiram with zinc ion inhibited the xenograft tumor growth of pancreatic cancer cells [27]. However, the direct effect of disulfiram on CSCs of PDACs in relation to ALDH is undetermined.…”

Section: Introductionmentioning

confidence: 99%

Reversing the Intractable Nature of Pancreatic Cancer by Selectively Targeting ALDH-High, Therapy-Resistant Cancer Cells

Kim

Lee

et al. 2013

PLoS ONE

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Human pancreatic ductal adenocarcinoma (PDAC) is a cancer with a dismal prognosis. The efficacy of PDAC anticancer therapies is often short-lived; however, there is little information on how this disease entity so frequently gains resistance to treatment. We adopted the concept of cancer stem cells (CSCs) to explain the mechanism of resistance and evaluated the efficacy of a candidate anticancer drug to target these therapy-resistant CSCs. We identified a subpopulation of cells in PDAC with CSC features that were enriched for aldehyde dehydrogenase (ALDH), a marker expressed in certain stem/progenitor cells. These cells were also highly resistant to, and were further enriched by, treatment with gemcitabine. Similarly, surgical specimens from PDAC patients showed that those who had undergone preoperative chemo-radiation therapy more frequently displayed cancers with ALDH strongly positive subpopulations compared with untreated patients. Importantly, these ALDH-high cancer cells were sensitive to disulfiram, an ALDH inhibitor, when tested in vitro. Furthermore, in vivo xenograft studies showed that the effect of disulfiram was additive to that of low-dose gemcitabine when applied in combination. In conclusion, human PDAC-derived cells that express high levels of ALDH show CSC features and have a key role in the development of resistance to anticancer therapies. Disulfiram can be used to suppress this therapy-resistant subpopulation.

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Gemcitabine response in pancreatic adenocarcinoma cells is synergistically enhanced by dithiocarbamate derivatives

Cited by 27 publications

References 27 publications

Procyanidin B2 3,3″‐di‐O‐gallate induces oxidative stress‐mediated cell death in prostate cancer cells via inhibiting MAP kinase phosphatase activity and activating ERK1/2 and AMPK

Procyanidin B2 3,3″‐di‐O‐gallate induces oxidative stress‐mediated cell death in prostate cancer cells via inhibiting MAP kinase phosphatase activity and activating ERK1/2 and AMPK

A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

Reversing the Intractable Nature of Pancreatic Cancer by Selectively Targeting ALDH-High, Therapy-Resistant Cancer Cells

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