Abstract
5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1456-1469.e6 |
| Journal | Cell Chemical Biology |
| Volume | 25 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 20 2018 |
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Keywords
- 5-nitrofurans
- ALDH
- BRAF inhibitor
- cancer stem cells
- drug mechanism of action
- drug targets
- melanoma
- nifuroxazide
- pro-drugs
- tumor-initiating cells
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmacology
- Drug Discovery
- Clinical Biochemistry
Cite this
ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells. / Sarvi, Sana; Crispin, Richard; Lu, Yuting; Zeng, Lifan; Hurley, Thomas; Houston, Douglas R.; von Kriegsheim, Alex; 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; Unciti-Broceta, Asier; Brunton, Valerie G.; Patton, E. Elizabeth.
In: Cell Chemical Biology, Vol. 25, No. 12, 20.12.2018, p. 1456-1469.e6.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells
AU - Sarvi, Sana
AU - Crispin, Richard
AU - Lu, Yuting
AU - Zeng, Lifan
AU - Hurley, Thomas
AU - Houston, Douglas R.
AU - von Kriegsheim, Alex
AU - Chen, Che Hong
AU - Mochly-Rosen, Daria
AU - Ranzani, Marco
AU - Mathers, Marie E.
AU - Xu, Xiaowei
AU - Xu, Wei
AU - Adams, David J.
AU - Carragher, Neil O.
AU - Fujita, Mayumi
AU - Schuchter, Lynn
AU - Unciti-Broceta, Asier
AU - Brunton, Valerie G.
AU - Patton, E. Elizabeth
PY - 2018/12/20
Y1 - 2018/12/20
N2 - 5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer.
AB - 5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer.
KW - 5-nitrofurans
KW - ALDH
KW - BRAF inhibitor
KW - cancer stem cells
KW - drug mechanism of action
KW - drug targets
KW - melanoma
KW - nifuroxazide
KW - pro-drugs
KW - tumor-initiating cells
UR - http://www.scopus.com/inward/record.url?scp=85058402204&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058402204&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2018.09.005
DO - 10.1016/j.chembiol.2018.09.005
M3 - Article
C2 - 30293938
AN - SCOPUS:85058402204
VL - 25
SP - 1456-1469.e6
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 12
ER -