Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition

Cruz-Bermúdez, Alberto; Laza-Briviesca, Raquel; Vicente-Blanco, Ramiro J.; García-Grande, Aránzazu; Coronado, María José; Laine-Menéndez, Sara; Palacios-Zambrano, Sara; Moreno-Villa, M. Rocío; Ruiz-Valdepeñas, Asunción Martín; Lendínez, Cristina; Romero, Atocha; Franco, Fernando; Calvo, Virginia; Alfaro, Cristina; Martín‐Acosta, Paloma; Salas, Clara; García, José M.; Provencio, Mariano

doi:10.1016/j.freeradbiomed.2019.03.009

Cited by 123 publications

(91 citation statements)

References 41 publications

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“…Cisplatin‐based doublets are widely used for NSCLC treatment and improve survival rates compared with placebo treatment (Rajeswaran, Trojan, Burnand, & Giannelli, ). However, the most important problem related to NSCLC therapy is intrinsic resistance to chemotherapeutics (Cruz‐Bermudez et al, ). The mechanisms of cisplatin resistance require further elucidation.…”

Section: Discussionmentioning

confidence: 99%

Rosmarinic acid reverses non‐small cell lung cancer cisplatin resistance by activating the MAPK signaling pathway

Liao

Gao

Sun

et al. 2020

Phytotherapy Research

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Cisplatin (DDP) is one of the first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC). However, repeated use of cisplatin in clinical practice often induces chemoresistance. The aims of this study were to investigate whether rosmarinic acid (RA) could reverse multidrug resistance (MDR) in NSCLC and to explore the underlying mechanisms. Our data demonstrated that RA significantly inhibited NSCLC cell proliferation and cell colony formation in a dose-dependent manner, induced G1 phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to DDP. Mechanistically, RA inhibited NSCLC cell growth, arrested cell cycle, and induced apoptosis by activating MAPK and inhibiting the expression of P-gp and MDR1, which correspondingly enhanced p21 and p53 expression. We observed that the growth of xenograft tumors derived from NSCLC cell lines in nude mice was significantly inhibited by combination therapy. We demonstrate that RA is a potentially effective MDR reversal agent for NSCLC, based on downregulation of MDR1 mRNA expression and P-gp. Together, these results emphasize the putative role of RA as a resistance reversal agent in NSCLC. K E Y W O R D S cisplatin, MAPK, multidrug resistance, non-small cell lung cancer, rosmarinic acid

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Section: Discussionmentioning

confidence: 99%

Rosmarinic acid reverses non‐small cell lung cancer cisplatin resistance by activating the MAPK signaling pathway

Liao

Gao

Sun

et al. 2020

Phytotherapy Research

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“…On the other hand, the increased ROS level in cancer cells might accelerates the development of tumor aggressiveness and drug resistance (Kumar et al, 2008). Increased ROS can activate cellular survival pathways including c-Myc-miR-137-EZH2 pathway , IL-11-JAK2-STAT5 pathway (Zhou et al, 2018), ATR-Chk1 pathway (Meng et al, 2018) and AXL (Oien et al, 2017) et al ROS may also mediate metabolism reprogramming (Cruz-Bermudez et al, 2019).…”

Section: Hypoxiamentioning

confidence: 99%

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

et al. 2020

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Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. However, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. The underlying mechanisms are incredibly complicated. Multiple transporters participate in the active transport of platinum-based antitumor agents, and the altered expression level, localization, or activity may severely decrease the cellular platinum accumulation. Detoxification components, which are commonly increasing in resistant tumor cells, can efficiently bind to platinum agents and prevent the formation of platinum-DNA adducts, but the adducts production is the determinant step for the cytotoxicity of platinum-based antitumor agents. Even if adequate adducts have formed, tumor cells still manage to survive through increased DNA repair processes or elevated apoptosis threshold. In addition, autophagy has a profound influence on platinum resistance. This review summarizes the critical participators of platinum resistance mechanisms mentioned above and highlights the most potential therapeutic targets or predicted markers. With a deeper understanding of the underlying resistance mechanisms, new solutions would be produced to extend the clinical application of platinum-based antitumor agents largely.

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“…PGC-1α is a transcription co-activator that regulates mitochondria biogenesis and it is involved in energy metabolism. It has been reported that CDDP treatment increases PGC-1α levels in a small cell lung carcinoma cell line and PGC-1α silencing sensitizes cells to this drug (109). Increased mitochondrial mass confers stem-like properties to breast cancer cell lines MDA-MB-231 and MCF7 and enables their resistance to paclitaxel (117).…”

Section: Targeting Mitochondria Metabolismmentioning

confidence: 99%

Metabolic Plasticity in Chemotherapy Resistance

et al. 2020

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Resistance of cancer cells to chemotherapy is the first cause of cancer-associated death. Thus, new strategies to deal with the evasion of drug response and to improve clinical outcomes are needed. Genetic and epigenetic mechanisms associated with uncontrolled cell growth result in metabolism reprogramming. Cancer cells enhance anabolic pathways and acquire the ability to use different carbon sources besides glucose. An oxygen and nutrient-poor tumor microenvironment determines metabolic interactions among normal cells, cancer cells and the immune system giving rise to metabolically heterogeneous tumors which will partially respond to metabolic therapy. Here we go into the best-known cancer metabolic profiles and discuss several studies that reported tumors sensitization to chemotherapy by modulating metabolic pathways. Uncovering metabolic dependencies across different chemotherapy treatments could help to rationalize the use of metabolic modulators to overcome therapy resistance.

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Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition

Cited by 123 publications

References 41 publications

Rosmarinic acid reverses non‐small cell lung cancer cisplatin resistance by activating the MAPK signaling pathway

Rosmarinic acid reverses non‐small cell lung cancer cisplatin resistance by activating the MAPK signaling pathway

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

Metabolic Plasticity in Chemotherapy Resistance

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