Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
Biochem Pharmacol. 2019 Apr;162:213-223. doi: 10.1016/j.bcp.2018.12.015. Epub 2018 Dec 19.
Microtubule targeting agents (MTAs) have been reported to manifest their cytotoxic effects not only in mitosis but also in interphase. However, the relationship between phase-specific susceptibility and MTA concentration, especially with respect to microtubule integrity, remains poorly defined. In addition, whether microtubule stabilizers and destabilizers act similarly or differ in the ability to induce interphase death is unclear. In order to resolve these uncertainties, we report here the results of a systematic comparison of primary acute lymphoblastic leukemia (ALL) and HeLa cells treated with three different MTAs, namely the microtubule stabilizer paclitaxel and two microtubule destabilizers, vincristine, and eribulin. Both types of cells were sensitive to each MTA, with IC values in the sub-nanomolar to low nanomolar range. Primary ALL cells arrested in mitosis when treated with paclitaxel at all tested concentrations, whereas the effects of vincristine or eribulin were concentration-dependent; low (<30 nM) concentrations induced mitotic death whereas higher concentrations (>100 nM) induced death directly in G1 phase. G1 phase death in response to higher concentrations of the destabilizers was associated with complete loss of interphase microtubule structure. In contrast, HeLa cells were only susceptible in M phase regardless of drug type or concentration. These results represent an important advance in our understanding and appreciation of microtubule function, and indicate that susceptibility to MTAs in G1 phase is both cell type- and drug type-restricted. The findings have important implications for the clinical use of MTAs especially in the context of drug combinations.
微管靶向剂（MTAs）已被报道不仅在有丝分裂中，而且在细胞间期中表现出细胞毒性作用。然而，相特异性敏感性与 MTA 浓度之间的关系，特别是与微管完整性有关的关系，仍然定义不明确。此外，微管稳定剂和微管不稳定剂在诱导细胞间死亡的能力方面是否相似或不同尚不清楚。为了解决这些不确定性，我们在此报告了用三种不同的 MTAs（即微管稳定剂紫杉醇和两种微管不稳定剂长春新碱和埃博霉素）处理原代急性淋巴细胞白血病（ALL）和 HeLa 细胞的系统比较结果。两种类型的细胞对每种 MTA 均敏感，IC 值在亚纳摩尔至低纳摩尔范围内。用紫杉醇处理时，原代 ALL 细胞在有丝分裂中被阻滞，而长春新碱或埃博霉素的作用则与浓度有关；低浓度（<30 nM）诱导有丝分裂死亡，而较高浓度（>100 nM）则直接诱导 G1 期死亡。对较高浓度的破坏剂的 G1 期死亡与间期微管结构的完全丧失有关。相比之下，HeLa 细胞无论药物类型或浓度如何，仅在 M 期易感。这些结果代表了我们对微管功能的理解和认识的重要进展，并表明 G1 期对 MTAs 的敏感性既受细胞类型限制，也受药物类型限制。这些发现对 MTAs 的临床应用具有重要意义，特别是在药物联合治疗的情况下。
