Abstract
BackgroundTemozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed strong anticancer potency in multiple cancer types. In this study, we aimed to clarify the relationship between TMZ-POH and autophagy, and explore the underlying mechanisms involved in.MethodsThe proteins involved in autophagy, mitochondrial fission, lysosomal function and membrane traffic were detected by western blots; Autophagosome, mitochondria and lysosome were visualized by transmission electron microscope (TEM) and immunostaining; Apoptosis analysis and fluorescence probe detection were applied by flow cytometry.ResultsTMZ-POH blocked mitophagy flux although the number of autophagosomes which colocalized with mitochondria in the cells was increased via inducing lysosomal dysfunction as evidence from impaired lysosomal acidification, maturation and hampered autophagosome- lysosome fusion, which largely depended on its downregulation on the small GTPase RAB7A via mevalonate pathway. More importantly, our data demonstrated TMZ-POH sensitized cancer cell to irradiation induced apoptosis.ConclusionsTemozolomide-perillyl alcohol conjugate impairs mitophagy flux by inducing lysosomal dysfunction in Non-Small Cell Lung Cancer (NSCLC) cells and sensitizes them to irradiation, thereby proposing TMZ-POH as a potential radiosensitizer.
Highlights
Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed strong anticancer potency in multiple cancer types
TMZ-POH impaired lysosomal acidification and maturation, and hampered autophagosome-lysosome fusion, which largely depended on its downregulation on the small GTPase Ras-associated binding protein 7A (RAB7A)
We found that TMZ-POH treatment increased intracellular autophagosomes compared to its individual constituents and their combination, as demonstrated by accumulation of LC3B-positive spot-like structures in above drug treated four non-small cell lung cancer (NSCLC) cells (Fig. 1b)
Summary
Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed strong anticancer potency in multiple cancer types. Accumulated ROS can cause mitochondrial damage and imbalance between mitochondrial fusion and fission. This imbalance can affect mitochondrial metabolism and functions, and initiates some protective mechanisms to removal dysfunctional mitochondria, such as autophagy, a conserved eukaryotic catabolic reaction that occurs continuously to remove and recycle damaged proteins and organelles, termed “mitophagy” [7]. LAMP1 and 2 are responsible to the fusion between autophagosomes and lysosomes Their deficiency arrests phagosomal maturation and blocks autophagosome-lysosome fusion due to the reduced ability to move toward the microtubule-organizing center [9]
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