Pfeiffer Anamarija, Di Leo Luca, Bechmann Marc Baker, Nawabi Mubeen, Ambjørner Sophie, Ardeshir-Larijani Diba, Colstrup Louise Thybo, Borchert Signe Vedel, Saaby Lasse, Brodin Birger, Gajhede Michael, Lund Xamuel Loft, Čečková Martina, Brünner Nils, Stenvang Jan
Biognosys AG, 8952 Schlieren, Switzerland.
Scandion Oncology A/S, Symbion, 2100 Copenhagen, Denmark.
Int J Mol Sci. 2025 Apr 17;26(8):3790. doi: 10.3390/ijms26083790.
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.
化疗耐药性，尤其是多药耐药性（MDR），仍然是有效癌症治疗的重大障碍，导致高死亡率。因此，开发针对关键分子机制以对抗耐药性的新型治疗策略是一项紧迫的临床需求。在本研究中，我们评估了小分子SCO-101恢复耐药癌细胞化疗敏感性的潜力。使用诸如分子对接、细胞活力、集落形成、染料外排、转运蛋白测定和化疗药物滞留等计算机模拟和体外模型，我们评估了SCO-101对几种耐药癌细胞中药物滞留和反应的影响。发现SCO-101可抑制乳腺癌耐药蛋白（BCRP/ABCG2）和尿苷二磷酸葡萄糖醛酸基转移酶家族1成员A1（UGT1A1）的活性，这两种关键蛋白通过细胞药物排泄和药物代谢参与耐药性。我们的结果表明，SCO-101对这些蛋白的抑制导致细胞内药物积累增加，增强了化疗药物的细胞毒性作用。此外，我们在非耐药模型中发现ABCG2高表达与MDR之间存在强相关性，其中ABCG2水平升高的细胞表现出化疗耐药性，而SCO-101联合治疗可有效逆转这种耐药性。这些发现突出了SCO-101通过抑制药物外排机制和代谢来克服MDR的治疗潜力，从而提高化疗疗效。SCO-101目前正在作为口服药物进行临床试验，被认为是改善耐药肿瘤患者癌症治疗结果的一种有前景的策略。
