Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Abstract

Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer.

Flavonoids: A Myth or a Reality for Cancer Therapy?

“…Autophagy is a highly conserved stress-induced catabolic process that positively regulates the cell death process. Several anticancer drugs triggered autophagy and, therefore, its induction represents a potential strategy for cancer therapy [75]. The aqueous extract of Allspice is rich in different types of flavonoids.…”

Autophagy activity in cholangiocarcinoma is associated with anatomical localization of the tumor

“…In CC, risk factors and tumor-specific signaling pathways, such as inflammatory or proliferative pathways, are known to support or inhibit autophagy [13,[15][16][17]. Since CC is a highly heterogeneous tumor [13,18], identification of molecular differences in CCs, classified as iCC, pCC and dCC, is needed, including autophagy activity. In line with this, we aimed to measure, compare, and correlate the expression of autophagy markers in tumorous and non-tumorous tissue samples of patients diagnosed with iCC, pCC, and dCC, and associate the levels of these markers with survival.…”

“…During tumorigenesis, autophagy may act as a suppressor by reducing the damaged cellular components and proteins, thus helping to maintain homeostasis [ 12 ]. In autophagy-deficient cells, however, the accumulation of damaged mitochondria may lead to increased production of reactive oxygen species (ROS) and inhibited autophagy may be associated with over-activated proliferation pathways, promoting cell growth [ 13 , 14 ]. On the other side, however, an active basal and an adaptive stress-induced autophagy, being present in established tumors [ 11 , 14 ], may promote tumor growth by maintaining tumor cell survival under stressful conditions.…”

Antitumor Efficacy of the Herbal Recipe Benja Amarit against Highly Invasive Cholangiocarcinoma by Inducing Apoptosis both In Vitro and In Vivo

“…Previous studies have shown that autophagy is considered as another response mechanism of CCA to several chemotherapy treatments [24][25][26]. Hence, in order to determine the effect of BJA-95 on the autophagy induction in CCA, autophagic vacuoles were imaged by fluorescence microscopy ( Figure 4A) and were then quantitated by flow cytometry ( Figure 4B).…”