Gambogic acid induces autophagy and combines synergistically with chloroquine to suppress pancreatic cancer by increasing the accumulation of reactive oxygen species
Furthermore, the inhibition of autophagy increased the GA-induced ROS production and led to apoptosis, thereby alleviating GA-induced cytoprotective autophagy and mitigating GA-resistance. Most remarkably, the combined treatment of CQ and GA showed the greatest antitumor effect in vivo. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer.
Therefore, to confirm the pharmacological induction of autophagic flux, LC3B-II expression levels must be greater after a dual autophagy initiation/inhibition than by either process acting alone. The anti-malarial drug chloroquine disrupts autophagy by inhibiting the acidification of the lysosomes that fuse with the autophagosomes, thus preventing the degradation of metabolic stress products and thereby inducing cellular apoptosis. Chloroquine-mediated inhibition of autophagy has been demonstrated in melanoma cell lines in vitro and in vivo subcutaneous tumor models. In vivo treatment in combination with Gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling resulting in reduced phosphorylation of ERK and STAT3. Our study demonstrates that via to date unreported effects chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates.
Various types of chemotherapeutics could reportedly induce autophagy in pancreatic cancer and lead to chemoresistance. In contrast, the results of the TUNEL assay showed that the combination group showed the highest levels of apoptosis in comparison to other groups.
These findings suggest that GA could directly and indirectly activate the caspase pathway. hydroxychloroquine – Our data also showed that GA induced protective autophagy, which limited its cytotoxicity.
1 Search results and study characteristics
Our previous study demonstrated that GA induced apoptosis by directly activating the caspase pathway. Intracellular accumulation of ROS can also induce apoptosis by activating the caspase pathway. The results of the present study showed that GA induced the expression of apoptosis-associated proteins by increasing ROS levels, and NAC was able to inhibit GA-induced apoptosis. The role of autophagy in pancreatic adenocarcinoma and the benefits of blocking it have recently been shown in a study in which animal survival was dramatically extended with chloroquine treatment against non-metastatic pancreatic adenocarcinoma. However, there is evidence that the role of this chemosensitization in pancreatic cancer is autophagydependent. Cell protective autophagy is reportedly induced by antitumor agents, and this can lead to the development of resistance to cancer therapy. Therefore, the inhibition of protective autophagy may enhance drug resistance.