Oliveira Thaís, Lemos Douglas, Jean Louise, Kawashima Jéssica M, de Azevedo Vitória R, Salustiano Eduardo J, Rumjanek Vivian M, Monteiro Robson Q
Laboratório de Trombose e Câncer, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Laboratório de Imunologia Tumoral, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Front Oncol. 2022 May 26;12:852985. doi: 10.3389/fonc.2022.852985. eCollection 2022.
Chronic Myeloid Leukemia is a neoplastic disease characterized by the abnormal expansion of hematopoietic cells with compromised functions. Leukemic cells often display a multidrug resistance phenotype, enabling them to evade a number of structurally unrelated cytotoxic compounds. One of those mechanisms relies on the high expression of efflux transporters, such as the ABC proteins, whose activity depends on the hydrolysis of ATP to reduce intracellular drug accumulation. In the present work, we employed a well-known erythroleukemia cell line, K562, and a multidrug resistant derivative cell, FEPS, to evaluate how hexokinase II, a key regulator for the rate-limiting step glycolysis, contributes to the establishment of the multidrug resistance phenotype. We found that multidrug resistant cells primarily resort to glycolysis to generate ATP. Clotrimazole reduced the expression of mitochondrial hexokinase II, which destabilized bioenergetic parameters such as reactive oxygen species production, ATP, and glutathione levels on multidrug resistant cells. This impaired the activity of ABCC1, leading to increased drug accumulation and cell death. In summary, we propose that decoupling of hexokinase II from the mitochondria emerges as a promising strategy to generate collateral sensitivity and aid in the management of chronic myeloid leukemia in chemotherapy-refractory patients.
慢性粒细胞白血病是一种肿瘤性疾病，其特征是造血细胞异常增殖且功能受损。白血病细胞通常表现出多药耐药表型，使其能够逃避多种结构不相关的细胞毒性化合物。其中一种机制依赖于外排转运蛋白的高表达，如ABC蛋白，其活性取决于ATP的水解以减少细胞内药物积累。在本研究中，我们使用了一种著名的红白血病细胞系K562和一种多药耐药衍生细胞FEPS，以评估糖酵解限速步骤的关键调节因子己糖激酶II如何促成多药耐药表型的形成。我们发现多药耐药细胞主要依靠糖酵解来产生ATP。克霉唑降低了线粒体己糖激酶II的表达，这破坏了多药耐药细胞的生物能量参数，如活性氧生成、ATP和谷胱甘肽水平。这损害了ABCC1的活性，导致药物积累增加和细胞死亡。总之，我们提出己糖激酶II与线粒体的解偶联是一种有前景的策略，可产生协同敏感性并有助于治疗化疗难治性慢性粒细胞白血病患者。
