Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia.
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia.
Genes (Basel). 2023 Oct 12;14(10):1931. doi: 10.3390/genes14101931.
Tyrosyl-DNA phosphodiesterase 1 and 2 (Tdp1 and Tdp2) are DNA repair enzymes that repair DNA damage caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reason for resistance to such widely used drugs such as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (-)-usnic acid. Both (+)- and (-)-enantiomers of compounds act equally effectively against Tdp1 with IC values in the range of 0.02-0.2 μM; only (-)-enantiomers inhibited Tdp2 with IC values in the range of 6-9 μM. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide (CC 3.0-3.9 μM in the presence of compounds and 2.4 μM the presence of DMSO) but potentiate it against Tdp2 knockout cells (CC 1.2-1.6 μM in the presence of compounds against 2.3 μM in the presence of DMSO). We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with the effective inhibition of Tdp1, which could take over the functions of Tdp2.
酪氨酸-DNA 磷酸二酯酶 1 和 2（Tdp1 和 Tdp2）是修复 DNA 损伤的酶，这些损伤是由各种试剂引起的，包括抗癌药物。因此，这些酶抵抗抗癌治疗，可能是对广泛使用的药物（如拓扑替康和依托泊苷）产生耐药性的原因。在本工作中，我们在(-)-usnic 酸衍生物中发现了能够抑制这两种酶的化合物。两种对映异构体（+)-和（-)-化合物对 Tdp1 的抑制作用同样有效，IC 值在 0.02-0.2 μM 范围内；只有（-)-对映异构体对 Tdp2 的抑制作用的 IC 值在 6-9 μM 范围内。令人惊讶的是，这些化合物在存在化合物时保护 HEK293FT 野生型细胞免受依托泊苷的细胞毒性作用（CC 在 3.0-3.9 μM 范围内，而在 DMSO 存在时为 2.4 μM），但对 Tdp2 敲除细胞具有增效作用（CC 在 1.2-1.6 μM 范围内，而在 DMSO 存在时为 2.3 μM）。我们假设在没有 Tdp2 的情况下化合物的增敏作用与 Tdp1 的有效抑制有关，Tdp1 可以接管 Tdp2 的功能。
