TY - JOUR

T1 - Soloxolone N-3-(Dimethylamino)propylamide Suppresses Tumor Growth and Mitigates Doxorubicin-Induced Hepatotoxicity in RLS40 Lymphosarcoma-Bearing Mice

AU - Moralev, Arseny D

AU - Sen'kova, Aleksandra V

AU - Firsova, Alina A

AU - Solomina, Daria E

AU - Rogachev, Artem D

AU - Salomatina, Oksana V

AU - Salakhutdinov, Nariman F

AU - Zenkova, Marina A

AU - Markov, Andrey V

N1 - This work was supported by the Russian Science Foundation (grant number 23-14-00374) (in silico, in vitro, and in vivo studies) and partly by the Russian state-funded project for ICBFM SB RAS (grant number 125012300659-6) (exploration of ROS-inducing activity of Sol-DMAP).

PY - 2025/12/10

Y1 - 2025/12/10

N2 - Multidrug resistance (MDR) remains a significant obstacle to effective cancer chemotherapy, primarily due to overexpression of P-glycoprotein (P-gp), which reduces intracellular accumulation of cytotoxic drugs. This study evaluated the pharmacological potential of the glycyrrhetinic acid derivative soloxolone N-3-(dimethylamino)propylamide (Sol-DMAP) as a biocompatible P-gp inhibitor with hepatoprotective properties. Using a murine model of P-gp-overexpressing RLS40 lymphosarcoma, we demonstrated that Sol-DMAP significantly enhanced the antitumor efficacy of doxorubicin (DOX) by increasing its intratumoral concentration 4.7-fold without enhancing systemic toxicity. Independently, Sol-DMAP exhibited direct antitumor activity, reducing tumor growth in vivo and inducing apoptosis and G1-phase arrest in RLS40 cells in vitro. In addition, Sol-DMAP mitigated DOX-induced hepatic injury by reducing necrotic and dystrophic changes in liver tissue and restoring heme oxygenase 1 (Hmox1) expression. Further studies in HepG2 cells confirmed that Sol-DMAP activated the NRF2-dependent antioxidant response, upregulating HMOX1, GCLC, GCLM, and NQO1 genes. Molecular docking revealed that Sol-DMAP can disrupt the KEAP1-NRF2 interaction, likely leading to NRF2 activation. Collectively, these findings demonstrate that Sol-DMAP effectively reverses P-gp-mediated MDR while protecting the liver from oxidative stress, highlighting its potential as a multifunctional scaffold for the development of safer and more effective chemotherapeutic adjuvants.

AB - Multidrug resistance (MDR) remains a significant obstacle to effective cancer chemotherapy, primarily due to overexpression of P-glycoprotein (P-gp), which reduces intracellular accumulation of cytotoxic drugs. This study evaluated the pharmacological potential of the glycyrrhetinic acid derivative soloxolone N-3-(dimethylamino)propylamide (Sol-DMAP) as a biocompatible P-gp inhibitor with hepatoprotective properties. Using a murine model of P-gp-overexpressing RLS40 lymphosarcoma, we demonstrated that Sol-DMAP significantly enhanced the antitumor efficacy of doxorubicin (DOX) by increasing its intratumoral concentration 4.7-fold without enhancing systemic toxicity. Independently, Sol-DMAP exhibited direct antitumor activity, reducing tumor growth in vivo and inducing apoptosis and G1-phase arrest in RLS40 cells in vitro. In addition, Sol-DMAP mitigated DOX-induced hepatic injury by reducing necrotic and dystrophic changes in liver tissue and restoring heme oxygenase 1 (Hmox1) expression. Further studies in HepG2 cells confirmed that Sol-DMAP activated the NRF2-dependent antioxidant response, upregulating HMOX1, GCLC, GCLM, and NQO1 genes. Molecular docking revealed that Sol-DMAP can disrupt the KEAP1-NRF2 interaction, likely leading to NRF2 activation. Collectively, these findings demonstrate that Sol-DMAP effectively reverses P-gp-mediated MDR while protecting the liver from oxidative stress, highlighting its potential as a multifunctional scaffold for the development of safer and more effective chemotherapeutic adjuvants.

KW - Animals

KW - Doxorubicin/adverse effects

KW - Mice

KW - Humans

KW - Chemical and Drug Induced Liver Injury/drug therapy

KW - NF-E2-Related Factor 2/metabolism

KW - Apoptosis/drug effects

KW - Hep G2 Cells

KW - Heme Oxygenase-1/metabolism

KW - Cell Line, Tumor

KW - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism

KW - Antineoplastic Agents/pharmacology

KW - Drug Resistance, Neoplasm/drug effects

KW - Male

KW - Liver/drug effects

KW - Xenograft Model Antitumor Assays

KW - Cell Proliferation/drug effects

UR - https://www.scopus.com/pages/publications/105025949408

U2 - 10.3390/ijms262411912

DO - 10.3390/ijms262411912

M3 - Article

C2 - 41465338

VL - 26

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 24

M1 - 11912

ER -