Evaluation of the toxicity of Caralluma europaea (C.E) extracts and their effects on apoptosis and chemoresistance in pancreatic cancer cells.

Pancreatic adenocarcinoma is a disease with no effective treatment. Chemo-resistance contributes to the dismal prognosis for patients diagnosed with the disease. This study aims to evaluate the toxicity and the effect of Caralluma europaea (C.E) extracts on cancer cell survival, apoptosis, chemo-resistance, and pro-cancer pathways, in pancreatic cancer. The acute and subacute toxicities of C.E extracts were evaluated. The cytotoxic effect on pancreatic cancer cell survival and apoptosis was determined by MTT assay and DNA fragmentation. The expression of cancer stemness markers was measured using Western blot. A molecular docking was used to test the possible effects of C.E compounds in inhibiting the Hedgehog and activating caspase-3. The hydroethanolic extract's DL50 was over 5000 mg/kg. During the subacute toxicity, only saponins extract showed some hepatic toxicity signs. Cells treated with C.E extracts combined with gemcitabine revealed an additive anti-survival activity. C.E extracts sensitized resistant MIA-PaCa-2 to gemcitabine treatment. Most of the C.E extracts downregulated the expression of cancer stemness-associated genes. Luteolin-7-O-glucoside presented the highest docking Gscore on human Smoothened. Isorhamnetin-3-O-rutinoside induced apoptosis via activation of caspase-3. C.E extracts can be considered safe in inhibiting pancreatic cancer cell survival, inducing apoptosis, and sensitizing cells to chemotherapy via Hedgehog inhibition and caspase-3 activation.Communicated by Ramaswamy H. Sarma.