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Creating synergies to enhance anti-tumor drug efficacy


Autophagy, from the Greek self-eating, is a catabolic process of regulated intracellular turnover in which cells degrade their own cytoplasmic components within lysosomes. In this process, cells form structures called phagophores, which expand and engulf cytoplasmic proteins and organelles in a double membrane vesicle named the autophagosome. Later, autophagosomes fuse with lysosomes to cause the degradation of their content. Metabolites like amino acids, lipids, sugars, can then be recycled e.g. for de novo synthesis of proteins or for ATP production. Autophagy occurs in all eukaryotic cells at a basal level and exercises cellular housekeeping by removing damaged organelles and protein aggregates. In the presence of stress stimuli like starvation, growth factor withdrawal or high energetic requirements, autophagy is rapidly upregulated allowing cells to cope with these changes.

Autophagy was found to be involved in diverse pathologies, including infections, neurodegeneration, aging, heart disease and cancer. In cancer cells, autophagy plays a complex and paradoxical role, having both tumor-suppressing and tumor-promoting properties. By removing damaged organelles and proteins from the cytoplasm, which are major sources of ROS, autophagy prevents DNA damage and genomic instability and thus, tumoral transformation. On the other hand, when a tumor is established, autophagy can contribute to its progression, by allowing cancer cells to survive stressful conditions and sustaining the metabolic reorganization that occurs in cells after oncogenic transformation. Given the important putative role of autophagy in tumor progression and maintenance, various preclinical and clinical studies have been undertaken or are in progress to develop therapeutic agents targeting autophagy. Despite this big development investment, the scientific community is highly debating whether the use of such drugs will produce a substantial gain in disease therapy as autophagy pathways are still poorly understood and it remains unclear if autophagy should be induced or suppressed in cancer. Most therapeutic strategies aimed at autophagy modulation in cancer are targeting autophagy inhibition due to well-characterized effects of autophagy on cell survival, but there are also studies supporting the opposite approach using autophagy inducers. In their recent work published in PLOS One, O’Donovan and colleagues, from the University College of Cork, examined the effect of two mechanistically different autophagy inducers, rapamycin and lithium, in apoptosis-incompetent cancer cells. Many types of cancers, particularly gastrointestinal tract cancers, are often resistant to cytotoxic therapy because tumor cells become deficient in apoptosis signaling but exhibit autophagy and after drug withdrawal, can recover leading to local or metastatic recurrence. In these cases, it is important to find strategies that limit autophagic survival and induce alternative cell death mechanisms. O’Donovan and colleagues evaluated the effects of lithium and rapamycin on autophagy induction and autophagic flux in apoptosis-incompetent esophageal and colorectal cancer cells. They chose several approaches including Enzo’s CYTO-ID® Autophagy detection kit, which contains a fluorescent dye that selectively labels autophagic vacuoles in live cells. Autophagic flux is the term used to describe the entire process of autophagy, from the onset to the fusion of autophagosome with lysosome and the subsequent breakdown of its cargo. If the accumulation of autophagosomes is due to a failure of cells to turnover autophagosomes, the addition of chloroquine, a lysosomotropic agent which inhibits lysosomal activity and blocks autophagosome turnover, will have no further effect on vesicle accumulation. Both lithium and rapamycin efficiently induced autophagosomes formation in the two tested cell lines but lithium only caused saturated or compromised autophagic flux. When combined with chemotherapeutic agents (5-fluorouracil, cisplatin or oxaliplatin), lithium showed strong enhancement of non-apoptotic cell death whereas rapamycin was protective. The chemosensitizing effect of lithium was also confirmed in vivo in a mouse colorectal cancer model. When each of the chemotherapeutic agents was combined with lithium a significant reduction in tumor volume was achieved. In addition, animal survival strongly increased when combination treatment was applied resulting in more than 50% of mice achieving long-term cure without tumor re-occurrence. Thus, combination treatment with lithium can substantially improve the efficacy of chemotherapeutic agents in apoptosis-deficient cancer cells. Moreover, lithium has a long history of safety in the clinic. Side effects are manageable and the authors found no evidence of lithium toxicity in mice. This makes lithium an interesting and promising compound for further studies.

The results of this study show that autophagy inducers cannot be considered as a single group, as their specific mechanism of action is critical: the inducer Rapamycin could not chemosensitize apoptosis-incompetent cancer cells, whereas lithium could. Derivatives of rapamycin, everolimus and temsirolimus have been approved by the FDA for the treatment of advanced/metastatic renal cell carcinoma. Preclinical studies with rapamycin showed both tumor growth inhibition and the ability of rapamycin to sensitize cells to apoptosis. The fact that these effects were not observed in the gastrointestinal cancer cells used in the study might indicate that different types of cancer and their context (origin, state, genetic make-up, microenvironment) play a role in the outcome of autophagy response and must be taken into consideration when using autophagy modulation in cancer therapy. Thus, the analysis of the possible role of autophagy in each type of cancer separately will likely be required to find out how to modulate autophagy in order to produce a beneficial effect.

Enzo Life Sciences offers a comprehensive product portfolio for advancing your research in autophagy and cancer including cellular analysis probes, antibodies, compound libraries, ELISA kits, some of which are listed below:

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Reference:

  1. T.R. O'Donovan, et al. Lithium Modulates Autophagy in Esophageal and Colorectal Cancer Cells and Enhances the Efficacy of Therapeutic Agents In Vitro and In Vivo. PLoS One. (2015) 10(8):e0134676.
  2. S. Lorin, et al. Autophagy regulation and its role in cancer. Semin Cancer Biol. (2013) 23(5):361-79.
  3. H. Cheong, et al. Therapeutic targets in cancer cell metabolism and autophagy. Nat Biotechnol. (2012) 30(7):671-8.

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