Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, Orissa, India.
Mol Pharm. 2011 Jun 6;8(3):852-66. doi: 10.1021/mp100455h. Epub 2011 Apr 15.
Doxorubicin (DOX) is a broad-spectrum anthracycline antibiotic used to treat a variety of cancers including leukemia. Chronic myeloid leukemia (CML) blasts like K562 cells are resistant to apoptosis induced by DOX due to several reasons, the primary being the sequestration of drug into cytoplasmic vesicles and induction of multidrug resistance (MDR) gene expression with DOX treatment resulting in intracellular resistance to this drug. Moreover, expression of antiapoptotic protein BCL-2 and the hybrid gene bcr/abl in K562 cells contributes resistance to DOX. Studies have shown that curcumin (CUR) has a pleiotropic therapeutic effect in cancer treatment, as it is an inhibitor of nuclear factor kappa B (NFκB) as well as a potent downregulator of MDR transporters. In this study, we investigated the potential benefit of using DOX and CUR in a single nanoparticle (NP) formulation to inhibit the development of drug resistance for the enhancement of antiproliferative activity of DOX in K562 cells. Results illustrate that the dual (DOX+CUR) drug loaded NPs were effectively delivered into K562 cells. CUR not only facilitates the retention of DOX in nucleus for a longer period of time but also inhibits the gradual expression of MDR1 and BCL-2 at the mRNA level in K562 cells. Moreover, Western blot results confirm that in combination both of the drugs were capable of inducing apoptosis even if in a lower concentration compared to either single drug in both solution or in formulation. Combinational therapy by using DOX and CUR, especially when administered in the NP formulation, has enhanced the cytotoxicity in K562 cells by promoting the apoptotic response. Overall, this combinational strategy has significant promise in the clinical management of intractable diseases, especially leukemia.
多柔比星（DOX）是一种广谱蒽环类抗生素，用于治疗多种癌症，包括白血病。慢性髓性白血病（CML）的母细胞样 K562 细胞由于多种原因对 DOX 诱导的细胞凋亡具有抗性，主要原因是药物被隔离到细胞质小泡中，并在 DOX 处理后诱导多药耐药（MDR）基因表达，导致细胞内对这种药物产生耐药性。此外，K562 细胞中抗凋亡蛋白 BCL-2 的表达和 bcr/abl 杂交基因也导致对 DOX 的耐药性。研究表明，姜黄素（CUR）在癌症治疗中具有多种治疗作用，因为它是核因子 kappa B（NFκB）的抑制剂，也是 MDR 转运蛋白的有效下调剂。在这项研究中，我们研究了在单个纳米颗粒（NP）制剂中使用 DOX 和 CUR 的潜在益处，以抑制耐药性的发展，从而增强 DOX 在 K562 细胞中的抗增殖活性。结果表明，双（DOX+CUR）载药 NP 有效地递送到 K562 细胞中。CUR 不仅促进 DOX 在核内更长时间的保留，而且还抑制 MDR1 和 BCL-2 在 K562 细胞中的 mRNA 水平的逐渐表达。此外，Western blot 结果证实，即使在溶液或制剂中的单药浓度较低的情况下，两种药物联合使用也能够诱导细胞凋亡。使用 DOX 和 CUR 的联合治疗，特别是在 NP 制剂中给药时，通过促进凋亡反应增强了 K562 细胞的细胞毒性。总的来说，这种联合策略在治疗难治性疾病，特别是白血病方面具有重要的临床应用前景。
