Introduction
Lung cancer is the leading cause of cancer‑associated mortalities worldwide[1]. Non-small cell lung cancer (NSCLC) accounts for 70-80% in all lung cancer cases [2]. Despite significant advances in diagnosis and treatment, the prognosis of lung cancer is still poor, with an overall 5-year survival rate of only 15%[3], making it one of the most deadly cancers in humans. In nowdays, chemotherapy has become the most commonly used treatment for lung cancer. However, chemotherapy has numerous adverse effects, including Multiplesystem multiple organ damage including Circulatory system, blood system, digestivesystem. Therefore, there is an urgent need for High effective and low toxic drugs for lung cancer treatment.
Norcantharidin (NCTD), a less-toxicity anabolic hormone analogue (CTD),is found in mylabris. Pharmacological studies have showed that CTD’s application is limited by gastrointestinal and urinary tract side effects [4]. A demethylated derivative of CTD, Norcantharidin (NCTD), was synthesized (Figure 1A) to replace CTD to reduce toxic side effects while still retaining the efficacy of CTD. Currently, NCTD has been widely used in China as an anti-tumor treatment. NCTD is more toxic to cancer cells than normal cells, which is different from traditional chemotherapy [5], Making this compound a potential for anticancer therapeutics. The NCTD has been showed to be related with apoptosis in sorts of cancers .Yet, the relationship between non-small cell lung cancer (NSCLC) and NCTD has not been thoroughly elucidated, although NCTD is involved in autophagy, the molecular mechanism is poorly understood. Previous studies have shown that autophagy plays an important role in the development of malignant tumors. Mitochondrial depolarization is a crucial early event in mitochondria[6].The mitophagic process is initiated to maintain cell line survival, but if cell is excessively damaged, mitophagy can also cause cell death[7]. In our study, we found that NCTD induced a decrease in the membrane potential of mitochondria (ΔΨm), activated AMPK and inhibited the PI3K/Akt/mTOR Molecular pathway, induced mitophagy and autophagy in A549 cells, and subsequently caused mitochondrial-dependent apoptosis.