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.