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

Abstract

Glutamine, like glucose, is a major nutrient consumed by cancer cells, yet these cells undergo glutamine starvation in the cores of tumors, forcing them to evolve adaptive metabolic responses. Pharmacologically targeting glutamine metabolism or withdrawal has been exploited for therapeutic purposes, but does not always induce cancer cell death. The mechanism by which cancer cells adapt to resist glutamine starvation in cisplatin-resistant non-small-cell lung cancer (NSCLC) also remains uncertain. Here, we report the potential metabolic vulnerabilities of A549/DDP (drug-resistant human lung adenocarcinoma cell lines) cells, which were more easily killed by the iron chelator deferoxamine (DFO) during glutamine deprivation than their parental cisplatin-sensitive A549 cells. We demonstrate that phenotype resistance to cisplatin is accompanied by adaptive responses during glutamine deprivation partly via higher levels of autophagic activity and apoptosis resistance characteristics. Moreover, this adaptation could be explained by sustained glucose instead of glutamine-dominant complex II-dependent oxidative phosphorylation (OXPHOS). Further investigation revealed that cisplatin-resistant cells sustain OXPHOS partly via iron metabolism reprogramming during glutamine deprivation. This reprogramming might be responsible for mitochondrial iron-sulfur [Fe-S] cluster biogenesis, which has become an “Achilles’ heel,” rendering cancer cells vulnerable to DFO-induced autophagic cell death and apoptosis through c-Jun N-terminal kinase (JNK) signaling. Finally, in vivo studies using xenograft mouse models also confirmed the growth-slowing effect of DFO. In summary, we have elucidated the adaptive responses of cisplatin-resistant NSCLC cells, which balanced stability and plasticity to overcome metabolic reprogramming and permitted them to survive under stress induced by chemotherapy or glutamine starvation. In addition, for the first time, we show that suppressing the growth of cisplatin-resistant NSCLC cells via iron chelator-induced autophagic cell death and apoptosis was possible with DFO treatment. These findings provide a solid basis for targeting mitochondria iron metabolism in cisplatin-resistant NSCLC for therapeutic purposes, and it is plausible to consider that DFO facilitates in the improvement of treatment responses in cisplatin-resistant NSCLC patients.

Cancer Drug Resistance: Targeting Proliferation or Programmed Cell Death

“…A549R, U1810R, and SKOV3R cells demonstrated statistically significant increases in IC50 compared with the wild-type cell line: the resistance index (RI = IC50 wild-type cells/IC50-resistant cells) was 1.6–2.4 ( Figure 2 A–C, Table S1 ). These results are consistent with the published data, which reveal 1.5–2-fold increases in IC50 for cisplatin-resistant cells obtained using a similar pulse-selection approach [ 16 , 17 ]. SW620R cells demonstrated an interesting exception (RI = 1) ( Figure 2 D, Table S1 ), which can be the result of unusual characteristics of this cell line and a questionable interpretation of the MTS assay that was previously described [ 16 , 22 , 25 ].…”

“…The cell lines U1810, A549, SKOV3, and SW620 were subsequently exposed to increasing concentrations (IC10, IC20, IC40, and IC50) of cisplatin for the development of resistance (Figure 1). resistant cells obtained using a similar pulse-selection approach [16,17]. SW620R cells demonstrated an interesting exception (RI = 1) (Figure 2D, Table S1), which can be the result of unusual characteristics of this cell line and a questionable interpretation of the MTS assay that was previously described [16,22,25].…”

“…Thus, this approach is considered to be a clinically relevant model. In this case, based on a comparison of IC50 values, an increase in resistance to anticancer agents is not too high (1.5–5-fold) [ 14 , 15 , 16 , 17 ]. Importantly, these data are in good consistency with resistant index for cancer cells derived from patients [ 13 ].…”

Overcoming Basal Autophagy, Kangai Injection Enhances Cisplatin Cytotoxicity by Regulating FOXO3a-Dependent Autophagic Cell Death and Apoptosis in Human Lung Adenocarcinoma A549/DDP Cells

“…After drug intervention or no drug intervention, A549 or A549/DDP cells were lysed and subjected to western blot analysis as a general method [16]. After treatment, the blots were probed with antibodies against Beclin 1, LC3, p62, cleaved caspase-3, p53, Bax, Bcl-2, FOXO3a, p-FOXO3a Ser253, p-FOXO3a Ser315, and p-FOXO3a Thr32; then, we detected the protein bands with ECL solution (Vazyme, Nanjing, China) using a Tanon 5200 imaging system (Tanon Science & Technology, Shanghai China) [17]. Total RNA was extracted from A549/DDP cells using a TRIzol reagent (TransGen Biotech, Beijing, China).…”

Trends in metabolic signaling pathways of tumor drug resistance: A scientometric analysis

“…Scholars have now discovered some metabolic pathways of the Warburg effect and potential targets of these pathways that can improve drug resistance ( 5 ). In addition to glycolysis, other metabolic pathways of drug resistance have also been extensively studied in recent years, such as the pentose phosphate pathway ( 6 ), glutamine metabolism ( 7 ), and lipid metabolism ( 8 ).…”