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

Ilana Chefetz; Edward Grimley; Kun Yang; Linda Hong; Ekaterina V. Vinogradova; Radu Suciu; Ilya Kovalenko; David Karnak; Cynthia A. Morgan; Mikhail Chtcherbinine; Cameron Buchman; Brandt Huddle; Scott Barraza; Meredith Morgan; Kara A. Bernstein; Euisik Yoon; David B. Lombard; Andrea Bild; Geeta Mehta; Iris Romero; Chun Yi Chiang; Charles Landen; Benjamin Cravatt; Thomas D. Hurley; Scott D. Larsen; Ronald J. Buckanovich

doi:10.1016/j.celrep.2019.02.032

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

Ilana Chefetz, Edward Grimley, Kun Yang, Linda Hong, Ekaterina V. Vinogradova, Radu Suciu, Ilya Kovalenko, David Karnak, Cynthia A. Morgan, Mikhail Chtcherbinine, Cameron Buchman, Brandt Huddle, Scott Barraza, Meredith Morgan, Kara A. Bernstein, Euisik Yoon, David B. Lombard, Andrea Bild, Geeta Mehta, Iris RomeroChun Yi Chiang, Charles Landen, Benjamin Cravatt, Thomas D. Hurley, Scott D. Larsen, Ronald J. Buckanovich

Yonsei Advanced Science Institute

Research output: Contribution to journal › Article › peer-review

71 Citations (Scopus)

Abstract

Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer “stemness,” and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness. We identified two ALDH1A family selective inhibitors (ALDH1Ai). ALDH1Ai preferentially kills CD133 ⁺ ovarian cancer stem-like cells (CSCs). ALDH1Ai induce necroptotic CSC death, mediated, in part, by the induction of mitochondrial uncoupling proteins and reduction in oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation capacity and increasing tumor eradication in vivo. These studies link ALDH1A with necroptosis and confirm the family as a critical therapeutic target to overcome chemotherapy resistance and improve patient outcomes.

Original language	English
Pages (from-to)	3061-3075.e6
Journal	Cell Reports
Volume	26
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2019.02.032
Publication status	Published - 2019 Mar 12

Bibliographical note

Funding Information:
The work was supported by the U.S. Department of Defense (grant OC130322) and the NIH (grant 5R01CA214567). Individual investigator support was as follows: Ann and Sol Schreiber Mentored grant and Liz Tilberis early career OCRA awards, the Marsha Rivkin Ovarian Center pilot award, and a WeRoc research grant from Foundation for Women's Cancer (to I.C.); University of Chicago-NIH CCSG (CA014599) and Ovarian Cancer SPORE (grant P50CA046592) (to I.R.); NIH (R01-AA18123 and R21-CA198409) (to T.D.H.); NIH (R01GM101171) and U.S. Department of Defense (OC140123) (to D.B.L.); and NIH (ES024872) and SU2C (SU2C-AACR-IRG-02-16) (to K.A.B.).

Funding Information:
The work was supported by the U.S. Department of Defense (grant OC130322 ) and the NIH (grant 5R01CA214567 ). Individual investigator support was as follows: Ann and Sol Schreiber Mentored grant and Liz Tilberis early career OCRA awards, the Marsha Rivkin Ovarian Center pilot award, and a WeRoc research grant from Foundation for Women's Cancer (to I.C.); University of Chicago-NIH CCSG ( CA014599 ) and Ovarian Cancer SPORE (grant P50CA046592 ) (to I.R.); NIH ( R01-AA18123 and R21-CA198409 ) (to T.D.H.); NIH ( R01GM101171 ) and U.S. Department of Defense ( OC140123 ) (to D.B.L.); and NIH ( ES024872 ) and SU2C ( SU2C-AACR-IRG-02-16 ) (to K.A.B.).

Publisher Copyright:
© 2019 The Author(s)

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

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10.1016/j.celrep.2019.02.032

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Chefetz, I., Grimley, E., Yang, K., Hong, L., Vinogradova, E. V., Suciu, R., Kovalenko, I., Karnak, D., Morgan, C. A., Chtcherbinine, M., Buchman, C., Huddle, B., Barraza, S., Morgan, M., Bernstein, K. A., Yoon, E., Lombard, D. B., Bild, A., Mehta, G., ... Buckanovich, R. J. (2019). A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells. Cell Reports, 26(11), 3061-3075.e6. https://doi.org/10.1016/j.celrep.2019.02.032

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title = "A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells",

abstract = " Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer “stemness,” and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness. We identified two ALDH1A family selective inhibitors (ALDH1Ai). ALDH1Ai preferentially kills CD133 + ovarian cancer stem-like cells (CSCs). ALDH1Ai induce necroptotic CSC death, mediated, in part, by the induction of mitochondrial uncoupling proteins and reduction in oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation capacity and increasing tumor eradication in vivo. These studies link ALDH1A with necroptosis and confirm the family as a critical therapeutic target to overcome chemotherapy resistance and improve patient outcomes.",

author = "Ilana Chefetz and Edward Grimley and Kun Yang and Linda Hong and Vinogradova, {Ekaterina V.} and Radu Suciu and Ilya Kovalenko and David Karnak and Morgan, {Cynthia A.} and Mikhail Chtcherbinine and Cameron Buchman and Brandt Huddle and Scott Barraza and Meredith Morgan and Bernstein, {Kara A.} and Euisik Yoon and Lombard, {David B.} and Andrea Bild and Geeta Mehta and Iris Romero and Chiang, {Chun Yi} and Charles Landen and Benjamin Cravatt and Hurley, {Thomas D.} and Larsen, {Scott D.} and Buckanovich, {Ronald J.}",

note = "Funding Information: The work was supported by the U.S. Department of Defense (grant OC130322) and the NIH (grant 5R01CA214567). Individual investigator support was as follows: Ann and Sol Schreiber Mentored grant and Liz Tilberis early career OCRA awards, the Marsha Rivkin Ovarian Center pilot award, and a WeRoc research grant from Foundation for Women's Cancer (to I.C.); University of Chicago-NIH CCSG (CA014599) and Ovarian Cancer SPORE (grant P50CA046592) (to I.R.); NIH (R01-AA18123 and R21-CA198409) (to T.D.H.); NIH (R01GM101171) and U.S. Department of Defense (OC140123) (to D.B.L.); and NIH (ES024872) and SU2C (SU2C-AACR-IRG-02-16) (to K.A.B.). Funding Information: The work was supported by the U.S. Department of Defense (grant OC130322 ) and the NIH (grant 5R01CA214567 ). Individual investigator support was as follows: Ann and Sol Schreiber Mentored grant and Liz Tilberis early career OCRA awards, the Marsha Rivkin Ovarian Center pilot award, and a WeRoc research grant from Foundation for Women's Cancer (to I.C.); University of Chicago-NIH CCSG ( CA014599 ) and Ovarian Cancer SPORE (grant P50CA046592 ) (to I.R.); NIH ( R01-AA18123 and R21-CA198409 ) (to T.D.H.); NIH ( R01GM101171 ) and U.S. Department of Defense ( OC140123 ) (to D.B.L.); and NIH ( ES024872 ) and SU2C ( SU2C-AACR-IRG-02-16 ) (to K.A.B.). Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = mar,

day = "12",

doi = "10.1016/j.celrep.2019.02.032",

language = "English",

volume = "26",

pages = "3061--3075.e6",

journal = "Cell Reports",

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Chefetz, I, Grimley, E, Yang, K, Hong, L, Vinogradova, EV, Suciu, R, Kovalenko, I, Karnak, D, Morgan, CA, Chtcherbinine, M, Buchman, C, Huddle, B, Barraza, S, Morgan, M, Bernstein, KA, Yoon, E, Lombard, DB, Bild, A, Mehta, G, Romero, I, Chiang, CY, Landen, C, Cravatt, B, Hurley, TD, Larsen, SD & Buckanovich, RJ 2019, 'A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells', Cell Reports, vol. 26, no. 11, pp. 3061-3075.e6. https://doi.org/10.1016/j.celrep.2019.02.032

TY - JOUR

T1 - A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells

AU - Chefetz, Ilana

AU - Grimley, Edward

AU - Yang, Kun

AU - Hong, Linda

AU - Vinogradova, Ekaterina V.

AU - Suciu, Radu

AU - Kovalenko, Ilya

AU - Karnak, David

AU - Morgan, Cynthia A.

AU - Chtcherbinine, Mikhail

AU - Buchman, Cameron

AU - Huddle, Brandt

AU - Barraza, Scott

AU - Morgan, Meredith

AU - Bernstein, Kara A.

AU - Yoon, Euisik

AU - Lombard, David B.

AU - Bild, Andrea

AU - Mehta, Geeta

AU - Romero, Iris

AU - Chiang, Chun Yi

AU - Landen, Charles

AU - Cravatt, Benjamin

AU - Hurley, Thomas D.

AU - Larsen, Scott D.

AU - Buckanovich, Ronald J.

N1 - Funding Information: The work was supported by the U.S. Department of Defense (grant OC130322) and the NIH (grant 5R01CA214567). Individual investigator support was as follows: Ann and Sol Schreiber Mentored grant and Liz Tilberis early career OCRA awards, the Marsha Rivkin Ovarian Center pilot award, and a WeRoc research grant from Foundation for Women's Cancer (to I.C.); University of Chicago-NIH CCSG (CA014599) and Ovarian Cancer SPORE (grant P50CA046592) (to I.R.); NIH (R01-AA18123 and R21-CA198409) (to T.D.H.); NIH (R01GM101171) and U.S. Department of Defense (OC140123) (to D.B.L.); and NIH (ES024872) and SU2C (SU2C-AACR-IRG-02-16) (to K.A.B.). Funding Information: The work was supported by the U.S. Department of Defense (grant OC130322 ) and the NIH (grant 5R01CA214567 ). Individual investigator support was as follows: Ann and Sol Schreiber Mentored grant and Liz Tilberis early career OCRA awards, the Marsha Rivkin Ovarian Center pilot award, and a WeRoc research grant from Foundation for Women's Cancer (to I.C.); University of Chicago-NIH CCSG ( CA014599 ) and Ovarian Cancer SPORE (grant P50CA046592 ) (to I.R.); NIH ( R01-AA18123 and R21-CA198409 ) (to T.D.H.); NIH ( R01GM101171 ) and U.S. Department of Defense ( OC140123 ) (to D.B.L.); and NIH ( ES024872 ) and SU2C ( SU2C-AACR-IRG-02-16 ) (to K.A.B.). Publisher Copyright: © 2019 The Author(s)

PY - 2019/3/12

Y1 - 2019/3/12

N2 - Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer “stemness,” and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness. We identified two ALDH1A family selective inhibitors (ALDH1Ai). ALDH1Ai preferentially kills CD133 + ovarian cancer stem-like cells (CSCs). ALDH1Ai induce necroptotic CSC death, mediated, in part, by the induction of mitochondrial uncoupling proteins and reduction in oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation capacity and increasing tumor eradication in vivo. These studies link ALDH1A with necroptosis and confirm the family as a critical therapeutic target to overcome chemotherapy resistance and improve patient outcomes.

AB - Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer “stemness,” and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness. We identified two ALDH1A family selective inhibitors (ALDH1Ai). ALDH1Ai preferentially kills CD133 + ovarian cancer stem-like cells (CSCs). ALDH1Ai induce necroptotic CSC death, mediated, in part, by the induction of mitochondrial uncoupling proteins and reduction in oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation capacity and increasing tumor eradication in vivo. These studies link ALDH1A with necroptosis and confirm the family as a critical therapeutic target to overcome chemotherapy resistance and improve patient outcomes.

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JO - Cell Reports

JF - Cell Reports

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ER -

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

Abstract

Bibliographical note

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UN SDGs

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