Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation

Guo, Fang; Yang, Zhijun; Kulbe, Hagen; Albers, Andreas; Sehouli, Jalid; Kaufmann, Andreas M.

doi:10.1016/j.biopha.2019.109371

Cited by 53 publications

(35 citation statements)

References 42 publications

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“…First, we were interested primarily in drugs effective against TICs, and this was seen with disulfiram. It was identified in the screen showing activity against spheroids more than adherent cells and while it has been classically used in the treatment of alcoholism [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

“…Elevated ALDH expression protects drug resistant TICs from elevated levels of ROS and inhibition of ALDH can cause ROS accumulation and genotoxic stress [ 47 ]. Disulfiram was recently investigated for its inhibitory effects on ALDH+ cell populations in OC in combination with cisplatin and was similarly found to increase intracellular ROS, which was further enhanced by the addition of exogenous copper [ 33 ]. In this study we showed that disulfiram did increase ROS in vitro but importantly it significantly reduced OC relapse in vivo after carboplatin treatment.…”

Section: Discussionmentioning

confidence: 99%

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Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model

Harrington

Ozaki

Caminear

et al. 2020

Cancers

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Disease recurrence is the major cause of morbidity and mortality of ovarian cancer (OC). In terms of maintenance therapies after platinum-based chemotherapy, PARP inhibitors significantly improve the overall survival of patients with BRCA mutations but is of little benefit to patients without homologous recombination deficiency (HRD). The stem-like tumor-initiating cell (TIC) population within OC tumors are thought to contribute to disease recurrence and chemoresistance. Therefore, there is a need to identify drugs that target TICs to prevent relapse in OC without HRD. RNA sequencing analysis of OC cells grown in TIC conditions revealed a strong enrichment of genes involved in drug metabolism, oxidative phosphorylation and reactive oxygen species (ROS) pathways. Concurrently, a high-throughput drug screen identified drugs that showed efficacy against OC cells grown as TICs compared to adherent cells. Four drugs were chosen that affected drug metabolism and ROS response: disulfiram, bardoxolone methyl, elesclomol and salinomycin. The drugs were tested in vitro for effects on viability, sphere formation and markers of stemness CD133 and ALDH in TICs compared to adherent cells. The compounds promoted ROS accumulation and oxidative stress and disulfiram, elesclomol and salinomycin increased cell death following carboplatin treatment compared to carboplatin alone. Disulfiram and salinomycin were effective in a post-surgery, post-chemotherapy OC relapse model in vivo, demonstrating that enhancing oxidative stress in TICs can prevent OC recurrence.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model

Harrington

Ozaki

Caminear

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…179,180 ALDH has also been reported to play a key role in maintaining the stemness of cancer cells, therefore explaining the anticancer effect of disulfiram in stem-like cancer cells. [181][182][183] In addition to ALDHrelated processes, disulfiram regulates copper-or zinc-dependent metabolism processes in cancer cells. 84,184 More and more evidence is indicating that disulfiram-mediated oxidative metabolism partially contributes to its anticancer activity.…”

Section: Non-oncology Drugs In Drug Repurposingmentioning

confidence: 99%

Overcoming cancer therapeutic bottleneck by drug repurposing

Zhang

Zhou

Xie

et al. 2020

Sig Transduct Target Ther

364

315

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Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The "treasure trove" of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono-or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.

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“…It was shown, that aldehyde dehydrogenases (ALDH) are important key players to maintain the role of CSCs [ 17 ], which includes inhibitors of ALDH as potential candidates for new therapeutic approaches. Recent studies show effective inhibition of ALDH through DSF as well as Cu(DDC) 2 treatment [ 18 , 19 , 20 , 21 ]. In this context, Cu(DDC) 2 is highlighted as a potential candidate.…”

Section: Introductionmentioning

confidence: 99%

Preclinical In Vitro Studies with 3D Spheroids to Evaluate Cu(DDC)2 Containing Liposomes for the Treatment of Neuroblastoma

2021

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Preclinical in vitro studies of drug candidates for anticancer therapy are generally conducted on well-established 2D cell models. Unfortunately, these models are unable to mimic the properties of in vivo tumors. However, in vitro 3D models (spheroids) have been proven to be superior in reflecting the tumor microenvironment. Diethyldithiocarbamate (DDC−) is the active metabolite of Disulfiram, an approved drug for alcoholism and repurposed for cancer treatment. DDC− binds copper in a molar ratio of 2:1 resulting in a water-insoluble Cu(DDC)2 complex exhibiting anticancer activities. Delivery of the Cu(DDC)2 complex using nanoparticulate carriers provides decisive advantages for a parental application. In this study, an injectable liposomal Cu(DDC)2 formulation was developed and the toxicity was compared with a 2D neuroblastoma and a 3D neuroblastoma cell model. Our results indicate that Cu(DDC)2 liposomes complied with the size requirements of nanoparticles for intravenous injection and demonstrated high drug to lipid ratios as well as colloidal stability upon storage. Furthermore, an efficient cytotoxic effect on neuroblastoma 2D cell cultures and a very promising and even more pronounced effect on 3D cell cultures in terms of neuroblastoma monoculture and neuroblastoma co-culture with primary cell lines was proven, highly encouraging the use of Cu(DDC)2 liposomes for anticancer therapy.

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Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation

Cited by 53 publications

References 42 publications

Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model

Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model

Overcoming cancer therapeutic bottleneck by drug repurposing

Preclinical In Vitro Studies with 3D Spheroids to Evaluate Cu(DDC)2 Containing Liposomes for the Treatment of Neuroblastoma

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