Shenmai Injection Supresses Glycolysis and Enhances Cisplatin Cytotoxicity in Cisplatin‐Resistant A549/DDP Cells via the AKT‐mTOR‐c‐Myc Signaling Pathway

Abstract

Tumor cells, especially drug-resistant cells, predominately support growth by glycolysis even under the condition of adequate oxygen, which is known as the Warburg effect. Glucose metabolism reprogramming is one of the main factors causing tumor resistance. Previous studies on Shenmai injection (SMI), a Chinese herbal medicine, have shown enhanced efficacy in the treatment of tumors in combination with chemotherapy drugs, but the mechanism is not clear. In this study, we investigated the effect of SMI combined with cisplatin on cisplatin-resistant lung adenocarcinoma A549/DDP cells. Our results showed that cisplatin-resistant A549/DDP cells exhibited increased glucose consumption, lactate production, and expression levels of key glycolytic enzymes, including hexokinase 2 (HK2), pyruvate kinase M1/2 (PKM1/2), pyruvate kinase M2 (PKM2), glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA), compared with cisplatin-sensitive A549 cells. SMI combined with cisplatin in A549/DDP cells, led to significantly lower expression levels of key glycolytic enzymes, such as HK2, PKM1/2, GLUT1, and pyruvate dehydrogenase (PDH). In addition, we found that the combination of SMI and cisplatin could inhibit cell proliferation and promote apoptosis by reducing the expression levels of p-Akt, p-mTOR, and c-Myc, and then, it reduced the glycolysis level. These results suggest that SMI enhances the antitumor effect of cisplatin via glucose metabolism reprogramming. Therefore, the combination of SMI and cisplatin may be a potential therapeutic strategy to treat cisplatin-resistant nonsmall cell lung cancer.

Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death

“…Alterations in cellular metabolism have emerged as a hallmark of cancer ( 14 ). Numerous studies have shown that cisplatin-resistant cells acquire drug resistance and undergo a major rewiring of their metabolism, as revealed by changes in enzymes that are involved in glucose and glutamine metabolism ( 3 , 15 , 16 ). Glutamine contributes to multiple biosynthetic pathways, supports the Krebs cycle and OXPHOS, and governs redox homeostasis ( 17 , 18 ).…”

A Multidimensional Bayesian Network Meta-Analysis of Chinese Herbal Injections for Treating Non-small Cell Lung Cancer With Gemcitabine and Cisplatin

“…[Liliaceae; Ophiopogonis radix]. A study ( Sun et al, 2020 ) have shown that Shenmai injection can reprogram glucose metabolism and enhance the sensitivity of lung cancer cells to chemotherapy drugs through the AKT/mTOR/c-Myc pathway. Ginsenoside Rg3, the main component of Shenmai injection, could decrease chemoresistance-induced expression of the programmed death ligand 1, increase immunomodulatory actions and response to DNA damage, and thereby inhibit tumorigenesis and viability of lung cancer cells ( Park et al, 2011 ; Jiang et al, 2017 ; Liu et al, 2019 ).…”

The Metabolism Reprogramming of microRNA Let-7-Mediated Glycolysis Contributes to Autophagy and Tumor Progression

“…The relatively low level of Let-7 expressed in a variety of cancers may explain the role of those Let-7 downstream molecules in the regulation of drug resistance. Inhibition of Let-7 has usually been observed in drug-resistant cells [ 65 , 66 ]. Li et al found that Let-7i was decreased in cisplatin-resistant lung cancer cells [ 67 ], consistent with the related expression of miR-202 , which was negatively correlated with imatinib-resistant ability [ 64 ].…”

“…Li et al found that Let-7i was decreased in cisplatin-resistant lung cancer cells [ 67 ], consistent with the related expression of miR-202 , which was negatively correlated with imatinib-resistant ability [ 64 ]. Several essential enzymes of glycolysis—including HK2, pyruvate kinase M1/2 (PKM1/2), GLUT1, and LDHA—were increased in the cisplatin-based resistant cell model [ 65 ]. The events of miR-202 targeting HK2 were consistently reported in hepatocellular carcinoma and pancreatic cancer [ 43 , 59 ].…”