Quinacrine synergizes with 5-fluorouracil and other therapies in colorectal cancer

Gallant, Jean‐Nicolas; Allen, Joshua E.; Smith, Charles D.; Dicker, David T.; Wang, Wenge; Dolloff, Nathan G.; Seyhan, Attila A.; El‐Deiry, Wafik S.

doi:10.4161/cbt.12.3.17034

Cited by 41 publications

(46 citation statements)

References 36 publications

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“…Simultaneous activation of p53 and suppression of the PI3K/AKT/mTOR and NF-κB pathways plays a key role in the anti-cancer activity of quinacrine (Wang et al, 2005;Gurova et al, 2005;Guo et al, 2009;Ehsanian et al, 2011;Gallant et al, 2011). Moreover, quinacrine-induced NFκB inactivation promotes TRAIL, oxaliplatin and 5-fluorouracil cytotoxicity in human colon carcinoma cell lines via growth inhibition (Jani et al, 2010;Gallant et al, 2011). Consistently, quinacrine is a chemosensitizer that can enhance chemotherapeutic drug-induced apoptosis of cancer cells (Friedman et al, 2007;Wang et al, 2010Wang et al, , 2011Wu et al, 2012).…”

Section: Introductionmentioning

confidence: 65%

“…Consistently, quinacrine is a chemosensitizer that can enhance chemotherapeutic drug-induced apoptosis of cancer cells (Friedman et al, 2007;Wang et al, 2010Wang et al, , 2011Wu et al, 2012). Noticeably, quinacrine-induced chemosensitization is primarily attributed to altered BCL2 family protein expression (Jani et al, 2010;Wang et al, 2010Wang et al, , 2011Gallant et al, 2011). In addition to suppression of NFκB-mediated MCL1 expression (Jani et al, 2010;Gallant et al, 2011;Wang et al, 2011), quinacrine down-regulated BCL2/BCL2L1 (also known as Bcl-xL) expression and/or up-regulated BAX, leading to cancer cell death (Wang et al, 2010;Preet et al, 2012).…”

Section: Introductionmentioning

confidence: 93%

“…Several studies suggest that the anti-cancer activity of quinacrine is not closely related to its DNA-binding ability, but is mediated through the suppression of survival signaling in cancer cells (Ehsanian et al, 2011). Simultaneous activation of p53 and suppression of the PI3K/AKT/mTOR and NF-κB pathways plays a key role in the anti-cancer activity of quinacrine (Wang et al, 2005;Gurova et al, 2005;Guo et al, 2009;Ehsanian et al, 2011;Gallant et al, 2011). Moreover, quinacrine-induced NFκB inactivation promotes TRAIL, oxaliplatin and 5-fluorouracil cytotoxicity in human colon carcinoma cell lines via growth inhibition (Jani et al, 2010;Gallant et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression

Changchien

Chen

Huang

et al. 2015

Toxicology and Applied Pharmacology

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Section: Introductionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression

Changchien

Chen

Huang

et al. 2015

Toxicology and Applied Pharmacology

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“…The combinatorial inhibitory effects of multiple drugs against CRC in vitro were assessed using a quantitative analysis of dose-response relationships as described previously 18 : multiples of the IC50 of each drug were used in non-constant ratio combinations and compared against the predicted effects for each drug alone. Combining effects of multiple doses was assessed by combination index (CI)-quantitative measurements based on the mass-action law of the degree of drug interaction that allows determination of synergism and antagonism for a given end point of the effect measurement based on Chou-Talalay analysis.…”

Section: Dose-response Assessment and Synergy Assessmentmentioning

confidence: 99%

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1a regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3b. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia. We found that palbociclib sensitizes colon cancer cells to hypoxia-induced apoptotic resistance via deregulation of HIF-1a accumulation. In addition to inhibition of cell proliferation, we observed that palbociclib promotes colon cancer cell death regardless of the presence of hypoxia at a comparatively high concentration via regulating ERK/GSK-3b signaling and GSK-3b expression. Furthermore, palbociclib synergized with irinotecan in a variety of colon cancer cell lines with various molecular subtypes via deregulating irinotecan-induced Rb phosphorylation and reducing HIF-1a accumulation under normoxia or hypoxia. Collectively, our findings provide a novel combination therapy strategy against hypoxic colon cancer cells that may be further translated in the clinic.

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“…3 Chemotherapy is not very effective in the treatment of metastatic colorectal cancer, with 5-year overall survival rates of less than 10%. 4 Thus, improved molecular targeted therapies are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Novel reversible selective inhibitor of nuclear export shows that CRM1 is a target in colorectal cancer cells

Niu

Chong

Han

et al. 2015

Cancer Biology & Therapy

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Abbreviations: CRM1, chromosomal region maintenance 1; DMSO, dimethyl sulfoxide; EGFR, epidermal growth factor receptor; LMB, leptomycin B; NES, leucine-rich nuclear export signal; PI3K, phosphoinositide 3-kinase; RanBP1, Ran-binding protein 1.Colorectal cancer arises via a multistep carcinogenic process and the deregulation of multiple pathways. Thus, the simultaneous targeting of multiple pathways may be a promising therapeutic approach for colorectal treatment. CRM1 is an attractive cancer drug target, because it can regulate multiple pathways and tumor suppressor proteins. In this study, we investigated the anti-tumor activity of a novel reversible CRM1 inhibitor S109 in colorectal cancer. Our data demonstrate that S109 inhibits proliferation and induces cell cycle arrest in colorectal cancer cells. Mechanistically, we demonstrate that the activity of S109 is associated with the nuclear retention of major tumor suppress proteins. Furthermore, the Cys528 mutation of CRM1 prevented the ability of S109 to block nuclear export and inhibit the proliferation of colorectal cancer cells. Interestingly, S109 decreased the CRM1 protein level via proteasomal pathway. We argue that reversible CRM1 inhibitors but not irreversible inhibitors can induce the degradation of CRM1, because the dissociation of reversible inhibitors of CRM1 changes the conformation of CRM1. Taken together, these findings demonstrate that CRM1 is a valid target for the treatment of colorectal cancer and provide a basis for the development of S109 therapies for colorectal cancer.

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Quinacrine synergizes with 5-fluorouracil and other therapies in colorectal cancer

Cited by 41 publications

References 36 publications

Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression

Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

Novel reversible selective inhibitor of nuclear export shows that CRM1 is a target in colorectal cancer cells

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