Autophagy (also known as macroautophagy) captures intracellular components in autophagosomes and delivers them to lysosomes, where they are degraded and recycled. Autophagy can have two functions in cancer. It can be tumour suppressive through the elimination of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. Alternatively, it can be tumour promoting in established cancers through autophagy-mediated intracellular recycling that provides substrates for metabolism and that maintains the functional pool of mitochondria. Therefore, defining the context-specific role for autophagy in cancer and the mechanisms involved will be important to guide autophagy-based therapeutic intervention.

/pdf/deconvoluting-the-context-dependent-role-for-autophagy-in-1o6tode44a.pdf

Deconvoluting the context-dependent role for autophagy in cancer

Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients.

/pdf/autophagy-and-chemotherapy-resistance-a-promising-2pz6sno24p.pdf

Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment

Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma

Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer

Autophagy is the process by which cellular material is delivered to lysosomes for degradation and recycling. There are three different types of autophagy, but macroautophagy, which involves the formation of double membrane vesicles that engulf proteins and organelles that fuse with lysosomes, is by far the most studied and is thought to have important context-dependent roles in cancer development, progression, and treatment. The roles of autophagy in cancer treatment are complicated by two important discoveries over the past few years. First, most (perhaps all) anticancer drugs, as well as ionizing radiation, affect autophagy. In most, but not all cases, these treatments increase autophagy in tumor cells. Second, autophagy affects the ability of tumor cells to die after drug treatment, but the effect of autophagy may be to promote or inhibit cell death, depending on context. Here we discuss recent research related to autophagy and cancer therapy with a focus on how these processes may be manipulated to improve cancer therapy.

https://molpharm.aspetjournals.org/content/molpharm/early/2014/02/26/mol.114.091850.full.pdf

Autophagy and Cancer Therapy

Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both ...

Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis.

A general and practical method for the synthesis of sulfonylated cinchona alkaloids is presented. The reaction was carried out via the Zn-mediated nucleophilic aromatic substitution of the N-oxides of quinoline core in cinchona alkaloids with sulfonyl chlorides. By a careful optimization of the reaction parameters and operation process, both aromatic and aliphatic sulfonly chlorides could react efficiently with the N-oxides to afford the sulfonylated products in high yields. In addition, the reaction could be reliably scaled up to gram level. As a result, the method provided a practical way for the synthesis of new cinchona alkaloid derivatives which might be potentially useful compounds, particularly in asymmetric catalysis.

Cheng Yu Gu

Papers

Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis.

Synthesis of Sulfonylated Cinchona Alkaloids via the Zn-Mediated Sulfonylation of the N-Oxides of the Quinoline Groups