Chemotherapy resistance, particularly multidrug resistance (MDR), remains a significant barrier to effective cancer treatment, leading to high mortality rates. The development of novel therapeutic strategies targeting key molecular mechanisms to counteract drug resistance is thus an urgent clinical need. In this study, we evaluated the potential of the small molecule SCO-101 to restore chemotherapy sensitivity in drug-resistant cancer cells. Using in silico and in vitro models such as molecular docking, cell viability, colony formation, dye efflux, transporter assays and chemotherapy retention, we assessed the impact of SCO-101 on drug retention and response in several drug-resistant cancer cells. SCO-101 was found to inhibit the activity of breast cancer resistance protein (BCRP/ABCG2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1), two key proteins involved in drug resistance by cellular drug excretion and drug metabolism. Our results demonstrate that inhibition of these proteins by SCO-101 leads to increased intracellular drug accumulation, enhancing the cytotoxic effects of chemotherapy agents. Additionally, we identified a strong correlation between high ABCG2 expression and MDR in non-drug-resistant models, where cells exhibiting elevated ABCG2 levels displayed chemotherapy resistance, which was effectively reversed by SCO-101 co-treatment. These findings highlight the therapeutic potential of SCO-101 in overcoming MDR by inhibiting drug efflux mechanisms and metabolism, thereby enhancing chemotherapy efficacy. SCO-101 is currently undergoing clinical trials as an orally administered drug and is considered a promising strategy for improving cancer treatment outcomes in patients with drug-resistant tumors.

• Klíčová slova
• ABCG2, BCRP, SCO-101, UGT1A1, cancer multidrug resistance,
• MeSH
• ABC transportér z rodiny G, člen 2 * antagonisté a inhibitory   metabolismus   chemie   MeSH
• chemorezistence * účinky léků   MeSH
• diketopiperaziny MeSH
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• lidé MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny * antagonisté a inhibitory   metabolismus   chemie   genetika   MeSH
• nádory * farmakoterapie   metabolismus   MeSH
• protinádorové látky * farmakologie   MeSH
• simulace molekulového dockingu MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester MeSH Prohlížeč
• ABC transportér z rodiny G, člen 2 * MeSH
• ABCG2 protein, human MeSH Prohlížeč
• diketopiperaziny MeSH
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• nádorové proteiny * MeSH
• protinádorové látky * MeSH