Natural small-molecule enhancers of autophagy induce autophagic cell death in apoptosis-defective cells

Abstract

Resistance of cancer cells to chemotherapy is a significant problem in oncology, and the development of sensitising agents or small-molecules with new mechanisms of action to kill these cells is needed. Autophagy is a cellular process responsible for the turnover of misfolded proteins or damaged organelles, and it also recycles nutrients to maintain energy levels for cell survival. In some apoptosis-resistant cancer cells, autophagy can also enhance the efficacy of anti-cancer drugs through autophagy-mediated mechanisms of cell death. Because the modulation of autophagic processes can be therapeutically useful to circumvent chemoresistance and enhance the effects of cancer treatment, the identification of novel autophagic enhancers for use in oncology is highly desirable. Many novel anti-cancer compounds have been isolated from natural products; therefore, we worked to discover natural, anti-cancer small-molecule enhancers of autophagy. Here, we have identified a group of natural alkaloid small-molecules that function as novel autophagic enhancers. These alkaloids, including liensinine, isoliensinine, dauricine and cepharanthine, stimulated AMPK-mTOR dependent induction of autophagy and autophagic cell death in a panel of apoptosis-resistant cells. Taken together, our work provides novel insights into the biological functions, mechanisms and potential therapeutic values of alkaloids for the induction of autophagy.

Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics

“…With respect to this interaction, Ajabnoor et al induced paclitaxel resistance in MCF-7 cells at clinically relevant drug doses with profound downregulation of apoptotic molecules and showed progressive mechanistic shift to autophagic death as the principal mechanism of druginduced cytotoxicity [124]. Similarly, naturally occurring alkaloid molecules, including isoliensinine, dauricine, and cepharanthine induce autophagic death in apoptosis-defective cells [125]. In most invasive carcinoma cases, particular molecules like PI3K, Akt, mTOR, NF-B, and MEK/ERK were aberrantly expressed, resulting in apoptotic resistance to various therapeutic approaches Fig.…”

A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission

“…14 More recently, natural compounds from alkaloids including liensinine exhibit anticancer effects through the modulation of MTOR-dependent autophagy. 15 However, the exact mechanism by which liensinine regulates autophagy in human breast cancer cells remains unclear.…”

Upregulation of Beclin-1 expression in DU-145 cells following low-frequency ultrasound irradiation combined with microbubbles

“…It was previously demonstrated that disorders in autophagy may lead to cancer; this may also be used as a type of anticancer therapy by promoting autophagic cell death in tumors (8). However, since the role of autophagy in cell survival and death remains unclear, further studies are required to determine its function (9).…”