Tigecycline targets nonsmall cell lung cancer through inhibition of mitochondrial function

Abstract

Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer with a high mortality rate and still remains therapeutically a challenge. A strategy to target NSCLC is to identify agents that are effective against NSCLC cells while sparing normal cells. We show that tigecycline, an FDA-approved antibiotic drug, preferentially targets NSCLC cells. Tigecycline is effective in inhibiting proliferation and inducing apoptosis of multiple cell lines derived from two common NSCLC subtypes: adenocarcinoma and squamous cell carcinoma. Tigecycline also dose-dependently inhibits colony formation of NSCLC subpopulation of cells with highly proliferative and invasive properties. Compared to NSCLC cells, tigecycline affects proliferation and survival of normal fibroblast cells significantly to a less extent. More importantly, tigecycline significantly inhibits NSCLC tumor growth through decreasing proliferation and increasing apoptosis of tumor cells in vivo. Tigecycline significantly inhibits mitochondrial respiration, mitochondrial membrane potential, and ATP levels and increases reactive oxygen species (ROS), suggesting that tigecycline impairs mitochondrial functions. Our study suggests that tigecycline may be a useful therapeutic agent, and inhibiting mitochondrial functions may represent a new targeted therapy for NSCLC.

Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress

“…In addition, our studies also add NPC to the growing list of artesunate‐targeted cancers. Various FDA‐approved drugs have been recently identified to be a potential anticancer candidate, such as tigecycline . In lines with these efforts, our work demonstrates the in vitro and in vivo efficacy of artesunate on NPC.…”

The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties

“…Apart from its anti-leukemic effect, recent studies have demonstrated that TIG could target multiple cancers by impairing mitochondrial functions (Lamb et al, 2015). For example, Jia et al (2016) found that TIG could significantly reduce growth and induce apoptosis in various NSCLC cell lines through inhibition of mitochondrial function. Inhibiting the mitochondrial gene expression and translation pathway by TIG could induce MYC oncogene-dependent tumor cell death, including the osteosarcomas (Oran et al, 2016) and lymphomas (D’Andrea et al, 2016).…”

Antibiotic tigecycline inhibits cell proliferation, migration and invasion via down‐regulating CCNE2 in pancreatic ductal adenocarcinoma

“…Previously, we also found that tigecycline inhibited cell metastasis in melanoma via blocking the EMT . Tigecycline was shown to induce intrinsic caspase‐dependent apoptosis in ALL, retinoblastoma, cervical squamous cell carcinoma and NSCLC . However, tigecycline did not cause significant apoptosis in PDAC cells when tigecycline was used alone.…”

“…Initially, tigecycline was shown to impair mitochondrial translation in AML, renal cell carcinoma and B‐cell lymphoma . Besides, tigecycline inhibited mitochondrial oxidative phosphorylation to restrict energy and/or oxidative stress and damage in chronic myeloid leukaemia stem cells, acute lymphoblastic leukaemia (ALL), non–small‐cell lung cancer (NSCLC) and hepatocellular carcinoma . However, tigecycline might have other targets in the cells except for proteins in mitochondria.…”

“…Then, we found that tigecycline also plays important roles in various solid tumours, such as gastric cancer, oral squamous cell carcinoma (OSCC), malignant melanoma, neuroblastoma and glioma . Meanwhile, other groups also found that tigecycline acts as a promising anti‐cancer drug for many other kinds of cancers, including triple‐negative breast cancer (TNBC), diffuse large B‐cell lymphomas (DLBCLs), cervical squamous cell carcinoma, ovarian cancer, hepatocellular carcinoma, chronic myeloid leukaemia (CML), prostate cancer and lung cancer . Recently, c‐Abl–specific tyrosine kinase inhibitors (TKIs) in combination with tigecycline were shown to be a promising strategy to treat patients with CML .…”