Nottingham Breast Cancer Research Centre, Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham, UK.
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, William Henry Duncan Building, Liverpool, UK.
J Cell Mol Med. 2022 Aug;26(16):4577-4590. doi: 10.1111/jcmm.17486. Epub 2022 Jul 16.
KP167 is a novel hypoxia-activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU-55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER of 1.60-3.42). KP167 induced greater radiosensitization in TNBC (SER 2.53 in MDAMB-231, 2.28 in MDAMB-468, 4.55 in MDAMB-436) and luminal spheroids (SER 1.46 in MCF-7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER of 1.56-2.37 compared with AQ4N SER of 1.13-1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs.
KP167 是一种新型的缺氧激活前药（HAP），通过 DNA 插入和烷化作用靶向癌细胞。在腔型和三阴性乳腺癌（TNBC）细胞系的 2D 和 3D 培养物中评估了 KP167 及其亲本对照物 AQ4N 的单药和放射增敏作用，并与 DNA 损伤修复抑制剂进行了比较。2D 常氧处理 DNA 修复抑制剂奥拉帕利或 KU-55933 导致了预期的显著放射增敏作用（增敏剂增强比，SER 为 1.60-3.42）。与 AQ4N 相比，KP167 在 TNBC（在 MDAMB-231 中为 SER2.53，在 MDAMB-468 中为 SER2.28，在 MDAMB-436 中为 SER4.55）和腔型球体（在 MCF-7 中为 SER1.46，在 T47D 细胞中为 SER1.76）中诱导了更大的放射增敏作用。在 2D 常氧条件下，使用 KP167 和 AQ4N 也获得了显著的放射增敏作用。尽管缺氧诱导了放射抵抗，但 KP167 在 2D 缺氧下的放射增敏作用仍然更大，产生的 SER 为 1.56-2.37，而 AQ4N 的 SER 为 1.13-1.94。这些数据表明 KP167 是一种有前途的单药和有效的常氧和缺氧乳腺癌细胞放射增敏剂，在 TNBC 中更有效。
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