Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma

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@article{8a36d6406dba4a57910761ef97843b1a,
title = "Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma",
abstract = "Despite highly toxic treatments, head and neck squamous cell carcinoma (HNSCC) have poor outcomes. There is an unmet need for more effective, less toxic therapies. Repurposing of clinically-approved drugs, with known safety profiles, may provide a time- and cost-effective approach to address this need. We have developed the AcceleraTED platform to repurpose drugs for HNSCC treatment; using in vitro assays (cell viability, clonogenic survival, apoptosis) and in vivo models (xenograft tumors in NOD/SCID/gamma mice). Screening a library of clinically-approved drugs identified the anti-malarial agent quinacrine as a candidate, which significantly reduced viability in a concentration dependent manner in five HNSCC cell lines (IC50 0.63-1.85 μM) and in six primary HNSCC samples (IC50 ~2 μM). Decreased clonogenic survival, increased apoptosis and accumulation of LC3-II (indicating altered autophagy) were also observed. Effects were additional to those resulting from standard treatments (cisplatin +/- irradiation) alone. In vivo, daily treatment with 100 mg/kg oral quinacrine plus cisplatin significantly inhibited tumor outgrowth, extending median time to reach maximum tumor volume from 20 to 32 days (p < 0.0001) versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone. Importantly, combination therapy enabled the dose of cisplatin to be halved to 1 mg/kg, whilst maintaining the same impairment of tumor growth. Treatment was well tolerated; murine plasma levels reached a steady concentration of 0.5 μg/mL, comparable to levels achievable and tolerated in humans. Consequently, due to its favorable toxicity profile and proven safety, quinacrine may be particularly useful in reducing cisplatin dose, especially in frail and older patients; warranting a clinical trial.",
keywords = "Drug repositioning, Drug repurposing, Head and neck cancer, Mepacrine, Quinacrine",
author = "Jennifer Bryant and Nikolaos Batis and Franke, {Anna Clara} and Gabriella Clancey and Margaret Hartley and Gordon Ryan and Jill Brooks and Southam, {Andrew D} and Nicholas Barnes and Joanna Parish and Sally Roberts and Farhat Khanim and Rachel Spruce and Hisham Mehanna",
year = "2019",
month = "8",
day = "27",
doi = "10.18632/oncotarget.27156",
language = "English",
volume = "10",
pages = "5229--5244",
journal = "OncoTarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "50",

}

RIS

TY - JOUR

T1 - Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma

AU - Bryant, Jennifer

AU - Batis, Nikolaos

AU - Franke, Anna Clara

AU - Clancey, Gabriella

AU - Hartley, Margaret

AU - Ryan, Gordon

AU - Brooks, Jill

AU - Southam, Andrew D

AU - Barnes, Nicholas

AU - Parish, Joanna

AU - Roberts, Sally

AU - Khanim, Farhat

AU - Spruce, Rachel

AU - Mehanna, Hisham

PY - 2019/8/27

Y1 - 2019/8/27

N2 - Despite highly toxic treatments, head and neck squamous cell carcinoma (HNSCC) have poor outcomes. There is an unmet need for more effective, less toxic therapies. Repurposing of clinically-approved drugs, with known safety profiles, may provide a time- and cost-effective approach to address this need. We have developed the AcceleraTED platform to repurpose drugs for HNSCC treatment; using in vitro assays (cell viability, clonogenic survival, apoptosis) and in vivo models (xenograft tumors in NOD/SCID/gamma mice). Screening a library of clinically-approved drugs identified the anti-malarial agent quinacrine as a candidate, which significantly reduced viability in a concentration dependent manner in five HNSCC cell lines (IC50 0.63-1.85 μM) and in six primary HNSCC samples (IC50 ~2 μM). Decreased clonogenic survival, increased apoptosis and accumulation of LC3-II (indicating altered autophagy) were also observed. Effects were additional to those resulting from standard treatments (cisplatin +/- irradiation) alone. In vivo, daily treatment with 100 mg/kg oral quinacrine plus cisplatin significantly inhibited tumor outgrowth, extending median time to reach maximum tumor volume from 20 to 32 days (p < 0.0001) versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone. Importantly, combination therapy enabled the dose of cisplatin to be halved to 1 mg/kg, whilst maintaining the same impairment of tumor growth. Treatment was well tolerated; murine plasma levels reached a steady concentration of 0.5 μg/mL, comparable to levels achievable and tolerated in humans. Consequently, due to its favorable toxicity profile and proven safety, quinacrine may be particularly useful in reducing cisplatin dose, especially in frail and older patients; warranting a clinical trial.

AB - Despite highly toxic treatments, head and neck squamous cell carcinoma (HNSCC) have poor outcomes. There is an unmet need for more effective, less toxic therapies. Repurposing of clinically-approved drugs, with known safety profiles, may provide a time- and cost-effective approach to address this need. We have developed the AcceleraTED platform to repurpose drugs for HNSCC treatment; using in vitro assays (cell viability, clonogenic survival, apoptosis) and in vivo models (xenograft tumors in NOD/SCID/gamma mice). Screening a library of clinically-approved drugs identified the anti-malarial agent quinacrine as a candidate, which significantly reduced viability in a concentration dependent manner in five HNSCC cell lines (IC50 0.63-1.85 μM) and in six primary HNSCC samples (IC50 ~2 μM). Decreased clonogenic survival, increased apoptosis and accumulation of LC3-II (indicating altered autophagy) were also observed. Effects were additional to those resulting from standard treatments (cisplatin +/- irradiation) alone. In vivo, daily treatment with 100 mg/kg oral quinacrine plus cisplatin significantly inhibited tumor outgrowth, extending median time to reach maximum tumor volume from 20 to 32 days (p < 0.0001) versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone. Importantly, combination therapy enabled the dose of cisplatin to be halved to 1 mg/kg, whilst maintaining the same impairment of tumor growth. Treatment was well tolerated; murine plasma levels reached a steady concentration of 0.5 μg/mL, comparable to levels achievable and tolerated in humans. Consequently, due to its favorable toxicity profile and proven safety, quinacrine may be particularly useful in reducing cisplatin dose, especially in frail and older patients; warranting a clinical trial.

KW - Drug repositioning

KW - Drug repurposing

KW - Head and neck cancer

KW - Mepacrine

KW - Quinacrine

UR - http://www.scopus.com/inward/record.url?scp=85071730236&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.27156

DO - 10.18632/oncotarget.27156

M3 - Article

C2 - 31497252

VL - 10

SP - 5229

EP - 5244

JO - OncoTarget

JF - OncoTarget

SN - 1949-2553

IS - 50

ER -