Multiple myeloma (MM) is an incurable malignant hematological neoplasm characterized by clonal proliferation of plasma cells accumulating in the bone marrow. Currently, the treatment of MM is usually based on a multi-drug combination strategy, and the remission rates of MM patients have been greatly improved. However, MM is still not immune to drug resistance and recurrence and is an incurable tumor. In this study, a comprehensive screen of the TCA cycle identified oxoglutarate dehydrogenase ( OGDH ) and pyruvate dehydrogenase E1 subunit alpha 1 ( PDHA1 ) as the most clinically relevant genes in MM, highlighting their potential as therapeutic targets. CPI-613, a novel non-redox-active lipoic acid analog that causes mitochondrial metabolism dysfunction by targeting OGDH and PDHA1, is currently in clinical trials in a variety of malignancies. In our study, CPI-613 was found to inhibit the proliferation of MM cells, and its combination with bortezomib (BTZ) produced a significant inhibitory effect at lower doses. In addition, CPI-613 can disrupt various mitochondrial functions, such as disrupting mitochondrial morphology, reducing oxidative phosphorylation, decreasing 5′- adenylate triphosphate production, and increasing reactive oxygen species, which ultimately leads to cell death mediated by the intrinsic apoptotic pathway in vitro. Furthermore, we found CPI-613 significantly inhibited tumor growth and induced intrinsic apoptosis in the MM mouse xenograft model. This study reveals the mechanism and effect of CPI-613 in MM, which suggests that CPI-613 may be a new drug option for the clinical treatment of MM, but further clinical trials are needed for evaluation.
Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy are urgently required. In this study, for effective pancreatic cancer therapy, a novel mitochondria-targeted and ROS-triggered drug delivery nanoplatform was developed from the TPP-TK-CPI-613 (TTCI) prodrug, in which the ROS-cleave thioketal functions as a linker connecting mitochondrial targeting ligand TPP and anti-mitochondrial metabolism agent CPI-613. DSPE-PEG2000 was added as an assistant component to increase accumulation in the tumor via the EPR effect. This new nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability, and robust therapeutic performances. With active mitochondrial targeting, the formulated nanoparticles (TTCINPs) demonstrate much higher accumulation in mitochondria, facilitating the targeted delivery of CPI-613 to its acting site. The results of in vitro antitumor activity and cell apoptosis revealed that the IC50values ofTTCINPs in three types of pancreatic cancer cells were around 20~30 µM, which was far lower than those of CPI-613 (200 µM); 50 µMTTCINPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy.Keywords:mitochondria-targeting;ROS-responsive;drug delivery;nanoparticles;pancreatic cancer therapy;CPI-613
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