Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

Abstract

Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

“…Autophagy can be induced in response to several stressors including: nutrient deprivation, chemotherapeutics, hypoxia, pathogen infection and endoplasmic reticulum stress (16)(17)(18). A larger body of research has reported that autophagy which is promoted by chemotherapeutic drugs in cancer cells, is related to drug-resistance of tumor cells (19)(20)(21). Autophagy is activated by doxorubicin in human colon cancer LoVo cells, and this autophagic activation reduces the sensitivity of cancer cells to doxorubicin (22).…”

Maslinic acid induces autophagy by down‐regulating HSPA8 in pancreatic cancer cells

“…Gemcitabine was reported to promote autophagy in pancreatic cancer cells; treatment with gemcitabine in PANC‐1 and MiaPaCa‐2 cells resulted in upregulation of the LC3‐II and observation of autophagesomes (Mukubou, Tsujimura, Sasaki, & Ku, ). However, recent studies showed that inhibition of autophagy is also a promising approach for the treatment in pancreatic cancer (Chude & Amaravadi, ; Monma et al, ; Xu et al, ; Yang & Kimmelman, ). Chloroquine inhibits autophagy in aggressive metastatic pancreatic adenocarcinoma by inhibiting the acidification of the lysosomes in aggressive pancreatic cancer cell lines S2VP10 (Frieboes, Huang, Yin, & McNally, ).…”

Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential

“…The combination treatment of deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer . Results suggest that autophagy functions as a survival mechanism during doxorubicin treatment.…”

“…The fractions of unchanged deguelin excreted via feces and urine were approximately 1.7% and 0.4%, respectively, and this suggested that it experienced an intensive metabolism after intravenous administration. More pharmacokinetic studies in different animal models should be conducted to further evaluate pharmacokinetic parameters of deguelin such as bioavailability, which would be useful for drug development …”