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Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones

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Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones. / Dyshlovoy, Sergey A; Pelageev, Dmitry N; Hauschild, Jessica; Borisova, Ksenia L; Kaune, Moritz; Krisp, Christoph; Venz, Simone; Sabutskii, Yurii E; Khmelevskaya, Ekaterina A; Busenbender, Tobias; Denisenko, Vladimir A; Pokhilo, Natalia D; Atopkina, Lyubov N; Graefen, Markus; Schlüter, Hartmut; Stonik, Valentin A; Bokemeyer, Carsten; Anufriev, Victor Ph; von Amsberg, Gunhild.

In: CANCERS, Vol. 11, No. 11, 1690, 30.10.2019.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Dyshlovoy, SA, Pelageev, DN, Hauschild, J, Borisova, KL, Kaune, M, Krisp, C, Venz, S, Sabutskii, YE, Khmelevskaya, EA, Busenbender, T, Denisenko, VA, Pokhilo, ND, Atopkina, LN, Graefen, M, Schlüter, H, Stonik, VA, Bokemeyer, C, Anufriev, VP & von Amsberg, G 2019, 'Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones', CANCERS, vol. 11, no. 11, 1690. https://doi.org/10.3390/cancers11111690

APA

Dyshlovoy, S. A., Pelageev, D. N., Hauschild, J., Borisova, K. L., Kaune, M., Krisp, C., Venz, S., Sabutskii, Y. E., Khmelevskaya, E. A., Busenbender, T., Denisenko, V. A., Pokhilo, N. D., Atopkina, L. N., Graefen, M., Schlüter, H., Stonik, V. A., Bokemeyer, C., Anufriev, V. P., & von Amsberg, G. (2019). Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones. CANCERS, 11(11), [1690]. https://doi.org/10.3390/cancers11111690

Vancouver

Dyshlovoy SA, Pelageev DN, Hauschild J, Borisova KL, Kaune M, Krisp C et al. Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones. CANCERS. 2019 Oct 30;11(11). 1690. https://doi.org/10.3390/cancers11111690

Bibtex

@article{caf6183808cb4a8a9fb8190fe7f4b22a,
title = "Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones",
abstract = "Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting. Mechanisms of action were examined by quantitative proteomics followed by bioinformatical analysis and target validation. Four synthesized molecules revealed the highest selectivity towards human CRPC cells, which correlated with higher GLUT-1 activity and expression. The compounds were able to induce pro-apoptotic signs and to inhibit the pro-survival processes and mechanisms of drug resistance (i.e., AR-signaling and autophagy). Proteome analysis suggested a disruption of the mitochondria/oxidative phosphorylation, which was validated by further functional analysis: thus, mitochondria depolarization, elevated levels of cytotoxic ROS, an increase of Bax/Bcl-2 ratio as well as release of mitochondrial AIF and cytochrome C to cytoplasm were observed. In conclusion, glucose-conjugated 1,4-naphthoquinones show potent activity and selectivity in human CRPC exerted via mitochondrial targeting. The compounds can overcome drug resistance against current standard therapies and suppress pro-survival mechanisms. This unique combination of properties makes them new promising candidates for the treatment of CRPC.",
keywords = "1,4-naphthoquinones, Castration-resistant prostate cancer, Mitochondria, Proteomics, Warburg effect",
author = "Dyshlovoy, {Sergey A} and Pelageev, {Dmitry N} and Jessica Hauschild and Borisova, {Ksenia L} and Moritz Kaune and Christoph Krisp and Simone Venz and Sabutskii, {Yurii E} and Khmelevskaya, {Ekaterina A} and Tobias Busenbender and Denisenko, {Vladimir A} and Pokhilo, {Natalia D} and Atopkina, {Lyubov N} and Markus Graefen and Hartmut Schl{\"u}ter and Stonik, {Valentin A} and Carsten Bokemeyer and Anufriev, {Victor Ph} and {von Amsberg}, Gunhild",
note = "Funding Information: Funding: This research was funded by Hamburger Krebsgesellschaft e.V. and RFBR grant No 18-33-00460_mol_a. Publisher Copyright: {\textcopyright} 2019 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2019",
month = oct,
day = "30",
doi = "10.3390/cancers11111690",
language = "English",
volume = "11",
journal = "CANCERS",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "11",

}

RIS

TY - JOUR

T1 - Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones

AU - Dyshlovoy, Sergey A

AU - Pelageev, Dmitry N

AU - Hauschild, Jessica

AU - Borisova, Ksenia L

AU - Kaune, Moritz

AU - Krisp, Christoph

AU - Venz, Simone

AU - Sabutskii, Yurii E

AU - Khmelevskaya, Ekaterina A

AU - Busenbender, Tobias

AU - Denisenko, Vladimir A

AU - Pokhilo, Natalia D

AU - Atopkina, Lyubov N

AU - Graefen, Markus

AU - Schlüter, Hartmut

AU - Stonik, Valentin A

AU - Bokemeyer, Carsten

AU - Anufriev, Victor Ph

AU - von Amsberg, Gunhild

N1 - Funding Information: Funding: This research was funded by Hamburger Krebsgesellschaft e.V. and RFBR grant No 18-33-00460_mol_a. Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/10/30

Y1 - 2019/10/30

N2 - Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting. Mechanisms of action were examined by quantitative proteomics followed by bioinformatical analysis and target validation. Four synthesized molecules revealed the highest selectivity towards human CRPC cells, which correlated with higher GLUT-1 activity and expression. The compounds were able to induce pro-apoptotic signs and to inhibit the pro-survival processes and mechanisms of drug resistance (i.e., AR-signaling and autophagy). Proteome analysis suggested a disruption of the mitochondria/oxidative phosphorylation, which was validated by further functional analysis: thus, mitochondria depolarization, elevated levels of cytotoxic ROS, an increase of Bax/Bcl-2 ratio as well as release of mitochondrial AIF and cytochrome C to cytoplasm were observed. In conclusion, glucose-conjugated 1,4-naphthoquinones show potent activity and selectivity in human CRPC exerted via mitochondrial targeting. The compounds can overcome drug resistance against current standard therapies and suppress pro-survival mechanisms. This unique combination of properties makes them new promising candidates for the treatment of CRPC.

AB - Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting. Mechanisms of action were examined by quantitative proteomics followed by bioinformatical analysis and target validation. Four synthesized molecules revealed the highest selectivity towards human CRPC cells, which correlated with higher GLUT-1 activity and expression. The compounds were able to induce pro-apoptotic signs and to inhibit the pro-survival processes and mechanisms of drug resistance (i.e., AR-signaling and autophagy). Proteome analysis suggested a disruption of the mitochondria/oxidative phosphorylation, which was validated by further functional analysis: thus, mitochondria depolarization, elevated levels of cytotoxic ROS, an increase of Bax/Bcl-2 ratio as well as release of mitochondrial AIF and cytochrome C to cytoplasm were observed. In conclusion, glucose-conjugated 1,4-naphthoquinones show potent activity and selectivity in human CRPC exerted via mitochondrial targeting. The compounds can overcome drug resistance against current standard therapies and suppress pro-survival mechanisms. This unique combination of properties makes them new promising candidates for the treatment of CRPC.

KW - 1,4-naphthoquinones

KW - Castration-resistant prostate cancer

KW - Mitochondria

KW - Proteomics

KW - Warburg effect

UR - http://www.scopus.com/inward/record.url?scp=85074474450&partnerID=8YFLogxK

U2 - 10.3390/cancers11111690

DO - 10.3390/cancers11111690

M3 - SCORING: Journal article

C2 - 31671612

VL - 11

JO - CANCERS

JF - CANCERS

SN - 2072-6694

IS - 11

M1 - 1690

ER -