ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells

Sarvi, Sana; Crispin, Richard; Lu, Yuting; Zeng, Lingqiu; Hurley, Thomas D.; Houston, Douglas R.; Kriegsheim, Alex von; Chen, Che‐Hong; Mochly‐Rosen, Daria; Ranzani, Marco; Mathers, Marie E.; Xu, Xiaowei; Xu, Wei; Adams, David J.; Carragher, Neil O.; Fujita, Mayumi; Schuchter, Lynn M.; Unciti‐Broceta, Asier; Brunton, Valerie G.; Patton, E. Elizabeth

doi:10.1016/j.chembiol.2018.09.005

Cited by 53 publications

(55 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Described effects are in disagreement with the previously reported antistemness impact of MEK1/2 inhibition in PEO1 cells [51], suggesting differences between cisplatinsensitive and cisplatin-resistant HGSOC cells. Consistent with our findings, ALDH1 overexpression in response to BRAF and MEK1/2 inhibition was recently reported in melanoma [68]. Given that high expression of ALDH1 and CD133 in ovarian tumors is strongly associated with poor prognosis and chemoresistance [69][70][71][72][73], we conclude that prolonged treatment of cisplatin-resistant HGSOC with trametinib might promote CSC enrichment.…”

Section: Trametinib Treatment Drastically Reduces the Growth Rates Ofsupporting

confidence: 92%

“…Because cells surviving trametinib treatment display very high ALDH1A expression and activity, combination with ALDH inhibitors may also offer benefit. This suggestion is further supported by increases in nifuroxazide sensitivity in melanoma cells overexpressing ALDH1 due to MEK1/2 inhibition [68]. Recently a selective inhibitor of the ALDH1A family was identified as a chemical agent capable of efficiently inducing necroptotic death in ovarian CSCs [23].…”

Section: Trametinib Treatment Drastically Reduces the Growth Rates Ofmentioning

confidence: 98%

See 1 more Smart Citation

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Chesnokov

Khan

Park

et al. 2019

Preprint

View full text Add to dashboard Cite

Rationale: High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rate of recurrence and acquired chemoresistance. Mutation and activation of the RAS/MAPK pathway has been linked to cancer cell proliferation and therapeutic resistance in numerous cancers. While RAS mutations are not commonly observed in HGSOC, less is known about downstream pathway activation. We therefore sought to investigate the role of MEK1/2 signaling in ovarian cancer.Methods: MEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines by using tissue microarray-based immunohistochemistry, immunoblotting, and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate, and stem-like characteristics. Xenografts were used in mice to investigate the effect of MEK1/2 inhibition on tumor growth in vivo. A drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy.Results: MEK1/2 signaling is active in a majority of HGSOC tissue samples and cell lines. MEK1/2 is further stimulated by cisplatin treatment, suggesting that MEK1/2 activation may play a role in chemotherapy resistance. The MEK1/2 inhibitor, trametinib, drastically inhibits MEK1/2 downstream signaling activity, causes prominent cell cycle arrest in the G1/0-phase in cell cultures, and reduces the rate of tumor growth in vivo, but does not induce cell death. Cells treated with trametinib display a high CD133 + fraction and increased expression of stemness-associated genes.Transient trametinib treatment causes long-term increases in a high ALDH1 activity subpopulation of cells that possess the capability of surviving and growing in non-adherent conditions. Conclusions: MEK1/2 inhibition in HGSOC cells efficiently inhibits proliferation and tumorgrowth and therefore may be a promising approach to suppress ovarian cancer cell growth. MEK1/2 inhibition promotes stem-like properties, thus suggesting a possible mechanism of resistance and that a combination with CSC-targeting drugs should be considered.

show abstract

Section: Trametinib Treatment Drastically Reduces the Growth Rates Ofsupporting

confidence: 92%

Section: Trametinib Treatment Drastically Reduces the Growth Rates Ofmentioning

confidence: 98%

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Chesnokov

Khan

Park

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Dimethyl ampal thiolester (DIMATE), an ALDH1 and ALDH3 inhibitor, depletes leukemia stem cells but, importantly, does not affect hematopoietic stem cells (Venton et al, 2016). More recently a potent ALDH1A1 selective inhibitor and a pan-ALDH1A inhibitor were found to synergize with chemotherapy (Huddle et al, 2018;Yang et al, 2018), whereas an ALDH-targeted pro-drug effectively eliminated ALDH bright melanoma cells (Sarvi et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…In these activities, the blocking of the STAT3 pathways plays an important role. Nifuroxazide can be effective as prophylaxis or second-line therapy for aGvHD (4)(5)(6)(7)(8)(28)(29)(30). It can be assumed that this old drug will find a new application in medicine.…”

Section: Resultsmentioning

confidence: 99%

Safety of oral nifuroxazide – analysis of data from a spontaneous reporting system

Karłowicz-Bodalska¹,

Głowacka²,

Boszkiewicz³

et al. 2019

Acta Poloniae Pharmaceutica - Drug Research

View full text Add to dashboard Cite

Nifuroxazide (4-hydroxy-benzoic acid; 2-[(5nitro-2-furanyl)methylene]hydrazide) is a chemotherapeutic agent belonging to the nitrofuran family. Indications for its use are acute and chronic bacterial diarrhea and other diseases with diarrhea (1). The drug has local antibacterial activity against some Gram-positive bacteria of the genus Staphylococcus and Gram-negative bacteria from the Enterobacteriaceae family: Yersinia spp., Escherichia spp., Enterobacter spp., Klebsiella spp. and Salmonella spp. It does not affect the bacteria Proteus vulgaris, Proteus mirabilis and Pseudomonas aeruginosa (1-3). Recently, attention has been paid to its antitumor potential in neuroblastoma, multiple myeloma, colorectal and breast cancer, efficacy in the treatment of graft-versus-host disease and nephroprotection in diabetes (4-10). The exact mechanism of action of nifuroxazide has not yet been identified. It probably has an inhibitory effect on dehydrogenase activity and protein synthesis in bacterial cells. Aldehyde dehydrogenase (ALDH) is responsible for the bioactivation of this prodrug. It has been found that nifuroxazide is a potent inhibitor of the Janus kinase 2 pathways and transcription factor 3 (JAK2/STAT3). It also has direct effects on oxidative stress and apoptosis (2, 4-6). Frequent self-administration of this drug by patients makes it necessary to pay attention to selfmedication, which in accordance with the guidelines of the World Health Organization is defined as ìusing medication by the consumer to treat signs/symptoms or minor health problems, recognized as such by themselvesî. In practice, this term also includes treatment by family members or friends, mainly, when the child is being treated (11). It should be responsible and safe, especially considering that diarrhea, in particular, acute diarrhea, is a serious problem of primary and hospital care. Itís serious complications, such as electrolyte disturbances, oligovolemic shock and even death, are dangerous especially for newborns, babies, small children and elderly people, due to their susceptibility to dehydration (12, 13). The fact that adverse effects inevitably accompany the desired therapeutic effects

show abstract

ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells

Cited by 53 publications

References 37 publications

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells

Safety of oral nifuroxazide – analysis of data from a spontaneous reporting system

Contact Info

Product

Resources

About