Vel has achieved significant clinical GSK1120212 benefit for multiple myeloma in clinical trials, but its effectiveness and administration have been limited by toxic side effect and development of resistance. Therefore, there is still a need to search for novel combination strategies to increase its effectiveness and decrease its toxic effects. Proteasome inhibition-based Regorafenib combinations have been paid much attention to produce greater clinical activity. Among the candidates identified in preclinical studies, combinations of proteasome inhibitors and HDAC inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical MM models and in many other human solid and hematologic cancer cell lines and xenografts. Combination therapy with Vel plus vorinostatin refractory MM have also been initiated in two phase I clinical trials. Although the combination of proteasome inhibitor and HDAC inhibitor has a great potential to be developed as anti-cancer therapy, the involved molecular mechanism is far from being understood. In living cells, L-carnitine, a biologically active form of carnitine, is required for the transport of fatty acids from the cytosol into the mitochondria to breakdown fatty acids for ATP generation. Without LC, it would be impossible to burn the amount of fat necessary to produce the energy. Because of its role as a regulator in the fat-burning process, LC plays an important role in regulating weight and increasing energy levels. Therefore LC has been widely used as a “keep fit” health supplement. It is also known that cancer cells predominantly produce energy by a high rate of glycolysis. We have recently reported that LC is a HDAC inhibitor, which selectively inhibits cancer cell growth in vivo and in vitro. In the current study, we investigated the synergistic effects of HDAC inhibitor LC and proteasome inhibitor Vel on cancer cell growth in vitro and in vivo, and explored the mechanism responsible for the combination-mediated cytotoxicity in cancer cells. Our findings confirmed that proteasome inhibitor and LC synergistically exert anti-cancer activity in vitro and in vivo, implying a great potential in future anti-cancer therapeutics. Our study also suggests a novel mechanism for the crosstalk between proteasome inhibition and LC-mediated protein acetylation. Combination therapy of proteasome inhibitor and HDAC inhibitor has been confirmed to be promising in cancer therapeutics. In the current study, we report that LC and Vel combination efficiently exerts anti-tumor effect both in vitro and in vivo. This has been confirmed by the following results. The combinationdecreased cell viability both in hetaptic HepG2 and SMMC-7721 cancer cells;induced cancer cell death in vitro detected by flow cytometry, morphological observation and PARP cleavage;inhibited tumor growth in vivo. Two models for the mechanism of enhancing cytotoxicity by HDAC inhibitors and proteasome inhibitors have been recently proposed. One model is that HDAC inhibitors promote proteasome inhibition-induced proteotoxic stress. By blocking the proteasome, proteasome inhibitors enhance the accumulation of damaged and misfolded proteins, thus inducing downstream free radical accumulation, ER stress and caspase activation; the second is that proteasome inhibitors enhance HDAC inhibition. In this model, HDAC inhibitors serves as the primary cytotoxic stimulus, perhaps by promoting expression of “death genes” via histone acetylation. Based on our findings, two pathways for the crosstalk between HDAC inhibition and proteasome inhibition have been proposed in this study.