Local anesthetic levobupivacaine induces ferroptosis and inhibits progression by up-regulating p53 in non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) is a common malignancy with high mortality and poor prognosis. Levobupivacaine is a widely used local anesthetic and presents potential anti-tumor activity. Nevertheless, the function of levobupivacaine in the NSCLC development remains elusive. Here, we tried to investigate the impact of levobupivacaine on the NSCLC progression and the underlying mechanism. Significantly, we revealed that levobupivacaine could inhibit the proliferation and induce the apoptosis of NSCLC cells. Levobupivacaine was able to attenuate the invasion and migration in the cells. Meanwhile, the treatment of levobupivacaine enhanced the erastin-induced inhibition of cell growth of NSCLC cells. The treatment of levobupivacaine remarkably increased the levels of ROS, iron, and Fe 2+ in NSCLC cells. Mechanically, levobupivacaine upregulated the expression of p53 and induced ferroptosis by regulating p53 in NSCLC cells. Moreover, tumorigenicity analysis in nude mice showed that the treatment of levobupivacaine significantly repressed the tumor growth of NSCLC cells in vivo. In summary, we concluded that the local anesthetic levobupivacaine inhibits the progression and induces ferroptosis of NSCLC by up-regulating p53. Our finding provides new insights into the mechanism by which levobupivacaine attenuates the development of NSCLC. Levobupivacaine may serve as a potential anti-tumor candidate for the therapeutic strategy of NSCLC.

Multifaceted Roles of Ferroptosis in Lung Diseases

“…Novel ferroptosis inhibitors, such as IKE and sorafenib, can inhibit the cystine/glutamate transporter, exhaust GSH, and increase sensitivity to radiotherapy (Li et al, 2020b;Ye et al, 2020). The local anesthetic levobupivacaine could increase p53 expression, enhance ferroptosis, and inhibit tumor growth in NSCLC (Meng et al, 2021). The dual PI3K/HDAC inhibitor BEBT-908 could activate immunogenic ferroptosis by hyperacetylating and activating p53 in lung cancer cells (Fan et al, 2021).…”

Post-Translational Modifications of p53 in Ferroptosis: Novel Pharmacological Targets for Cancer Therapy

“…Flubendazole, an antimalarial drug, inhibits SLC7A11/GPX4, promoting ferroptosis in castration-resistant prostate cancer ( Zhou et al, 2021 ). Levobupivacaine, distinct from its anesthetic effect, inhibits SLC7A11/GPX4 and promotes p53-mediated ferroptosis to exert an antitumor effect in non-small cell lung cancer ( Meng et al, 2021 ). Besides, other targets can also be utilized.…”

Drug Repurposing: The Mechanisms and Signaling Pathways of Anti-Cancer Effects of Anesthetics

“…Since treatment of levobupivacaine regulates ROS generation, Meng et al revealed that levobupivacaine treatment inhibits proliferation and induces apoptosis of NSCLC cancer cell lines. They also discovered that treatment of levobupivacaine upregulates ROS, iron, and Fe 2+ in NSCLC cells which in turn induces ferroptosis [ 75 ]. This levobupivacaine-induced ferroptosis is mediated by up-regulation of P53.…”