title: Development of targeting lonidamine liposomes that circumvent drug-resistant cancer by acting on mitochondrial signaling pathways.
abstract: Even when faced with elimination, functional materials may offer new alternatives to expensive drugs. Once used to treat benign prostate hypertrophy, the US Food and Drug Administration (FDA) suspended the use of lonidamine due to the occurrence of liver problems arising from its poor pharmaceutical properties. The objectives of the present study were to develop targeting lonidamine liposomes in combination with targeting epirubicin liposomes to circumvent drug-resistant cancer. Evaluations were performed on A549 and drug-resistant A549cDDP lung cancer cells and drug-resistant A549cDDP xenografted BALB/c nude mice. A DQA-PEG(2000)-DSPE conjugate was incorporated onto the liposomes as a targeting molecule. The constructed targeting lonidamine liposomes and targeting epirubicin liposomes measured were approximately 80 nm. The targeting lonidamine liposomes significantly enhanced the inhibitory effect of the targeting epirubicin liposomes in the drug-resistant A549cDDP cells in a lonidamine dose-dependent manner. Mechanism studies revealed that the targeting liposomes were selectively accumulated in the mitochondria, dissipating the mitochondrial membrane potential, opening the mitochondrial permeability transition pores, and releasing cytochrome C by translocation. This initiated a cascade of caspase 9 and 3 reactions and activated the pro-apoptotic Bax protein while suppressing the anti-apoptotic Mcl-1 protein, thereby enhancing the cytotoxic effect by acting on the mitochondrial signaling pathways. The efficacy in treating the drug-resistant A549cDDP xenografted tumor model after administration of the targeting lonidamine liposomes plus targeting epirubicin liposomes was the most significant compared with the administration of the controls at comparable doses. In conclusion, targeting lonidamine liposomes could be used as a potent co-therapy with an anticancer agent to enhance the efficacy of treating drug-resistant cancer by acting on the mitochondrial signaling pathways.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Nan
authors: N
authors: Li
authors: Cheng-Xiang
authors: CX
authors: Zhang
authors: Xiao-Xing
authors: XX
authors: Wang
authors: Liang
authors: L
authors: Zhang
authors: Xu
authors: X
authors: Ma
authors: Jia
authors: J
authors: Zhou
authors: Rui-Jun
authors: RJ
authors: Ju
authors: Xiu-Ying
authors: XY
authors: Li
authors: Wei-Yu
authors: WY
authors: Zhao
authors: Wan-Liang
authors: WL
authors: Lu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D015251:Epirubicin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008081:Liposomes / Q000737:chemistry*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D008081:Liposomes; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D015251:Epirubicin; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D020169:Caspases; C016371:lonidamine