Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis

Abstract

Metabolic reprogramming has been recognized as an essential emerging cancer hallmark. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been reported to have anti-cancer effects by reversing tumor-associated glycolysis. This study was performed to explore the anti-cancer potential of DCA in lung cancer alone and in combination with chemo- and targeted therapies using two non-small cell lung cancer (NSCLC) cell lines, namely, A549 and LNM35. DCA markedly caused a concentration- and time-dependent decrease in the viability and colony growth of A549 and LNM35 cells in vitro. DCA also reduced the growth of tumor xenografts in both a chick embryo chorioallantoic membrane and nude mice models in vivo. Furthermore, DCA decreased the angiogenic capacity of human umbilical vein endothelial cells in vitro. On the other hand, DCA did not inhibit the in vitro cellular migration and invasion and the in vivo incidence and growth of axillary lymph nodes metastases in nude mice. Treatment with DCA did not show any toxicity in chick embryos and nude mice. Finally, we demonstrated that DCA significantly enhanced the anti-cancer effect of cisplatin in LNM35. In addition, the combination of DCA with gefitinib or erlotinib leads to additive effects on the inhibition of LNM35 colony growth after seven days of treatment and to synergistic effects on the inhibition of A549 colony growth after 14 days of treatment. Collectively, this study demonstrates that DCA is a safe and promising therapeutic agent for lung cancer.

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

“…These include drugs targeting ETC, TCA, glycolysis, and fatty acid oxidation and synthesis enzymes. Some of these enzymes are localized in the mitochondria, whereas others are found in the cytosol (Figure 1 and Table 3) [7,[428][429][430][431][432][433][434][435][436][437][438]. In addition, increasing mitochondrial ROS production is also an important mitochondria-related cancer therapy strategy [14,20].…”

Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo

“…Synergism has been reported when DCA is combined with different drugs for anti-cancer research: DCA/cisplatin or gefitnib or elotinib ( Al-Azawi et al, 2021 ), DCA/metformin ( Kim et al, 2021 ; Klose et al, 2021 ; Korsakova et al, 2021 ), DCA/3-bromopyruvate ( Nikravesh et al, 2021 ), DCA/sorafenib ( Sun et al, 2021 ), DCA/PX-478 ( Parczyk et al, 2021 ) and DCA/erlotinib ( Dyrstad et al, 2021 ). Said synergistic effect has also been observed when Nic is combined with other agents: Nic/gemcitabine ( Guo et al, 2022b ), Nic/metformin ( Kang et al, 2021 ) and Nic/doxorubicin ( Lohiya and Katti, 2021 ).…”

PD-1 Independent Role of PD-L1 in Triple-Negative Breast Cancer Progression

“…The bottom chamber in the system was filled with media supplemented with 10% FBS as a chemo-attractant and then incubated at 37 °C for 24 h. Non-invasive cells were removed from the upper surface of the filter by gently rubbing the area with a cotton swab. Cells that invaded the Matrigel and passed through the 8 µm pores of the insert were detected using CellTiter-Glo ® Luminescent Cell Viability assay (Promega Corporation, Madison, WI, USA) as previously described [ 71 ]. The impact of PD-L1 knockout on cellular invasion was presented as a percentage (%) by comparing the invasiveness of PD-L1- knockout cells to the control cells.…”