Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticles
Conventional anti-cancer drugs, including doxorubicin, are associated with high toxicity and non-specific distribution in the body which results in a cascade of side effects. Cancer cells can utilize autophagy to promote tolerance to the stress induced by anti-cancer agents; this may be the major ca...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | OpenNano |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S235295202300021X |
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| author | Mohammed Numan Alamassi Suet Lin Chia Che Azurahanim Che Abdullah Mas Jaffri Masarudin |
| author_facet | Mohammed Numan Alamassi Suet Lin Chia Che Azurahanim Che Abdullah Mas Jaffri Masarudin |
| author_sort | Mohammed Numan Alamassi |
| collection | DOAJ |
| description | Conventional anti-cancer drugs, including doxorubicin, are associated with high toxicity and non-specific distribution in the body which results in a cascade of side effects. Cancer cells can utilize autophagy to promote tolerance to the stress induced by anti-cancer agents; this may be the major cause of drug resistance in advanced tumors. Owing to the molecular dynamism of cancer cells, targeting the pro-apoptotic survival pathways such as autophagy may increase the effectiveness of existing therapeutic agents at lower concentrations, thereby reducing the side effects of such agents. SAR405 is an inhibitor of autophagy activity due to its molecular interactions within the ATP binding site; however, it suffers from extracellular premature degradation and poor cellular uptake. Conversely, chitosan nanoparticles are considered biologically degradable, non-toxic, and biocompatible drug delivery agents that can be used to minimize the side effects of conventional therapeutic agents whilst increasing their intracellular uptake. In this study, a binary therapeutic strategy for the enhancement of the efficacy of doxorubicin while simultaneously inhibiting autophagy via a nano-mediated delivery system is reported. Autophagic inhibition was achieved via the improvement of SAR405 cellular uptake using SAR405-loaded chitosan nanoparticles. The synthesized nanoparticles were subsequently characterized for parameters of hydrodynamic diameter and polydispersity, while encapsulation and drug loading efficiencies were determined. Morphological characterization of the nanoparticles was elucidated using electron microscopy, and the cytotoxicity of the SAR405-loaded chitosan nanoparticles in combination treatments with doxorubicin was assessed through MTT and Annexin-v apoptosis assays. Autophagy progression through autophagosome formation was also evaluated using CYTO-ID staining. Following encapsulation, the size of the SAR405-loaded chitosan nanoparticles significantly increased from 54 nm to 161 nm at 10 µM SAR405 concentration, while the polydispersity index increased from 0.11 to 0.31 denoting presence of both encapsulated and unencapsulated moieties. When A549 lung cancer cells were treated with the IC50 values of doxorubicin in combination with SAR405-encapsulated CNP, an approximately 47% more reduction in cell viability was observed via the Annexin V-FITC/PI assay compared to using doxorubicin alone. Inhibition of autophagy was also detected in cells treated with SAR405 delivered using the nanoparticle system and was thought to be the primary reason towards a decrease in the resistance of the cancer cells to doxorubicin and thus increased its efficacy at lower concentrations. Therefore, this study has demonstrated a potential way of targeting cancer cell survival pathways that can be considered an effective way of increasing the efficacy of chemotherapeutic drugs. |
| first_indexed | 2024-04-09T15:30:20Z |
| format | Article |
| id | doaj.art-9be6db3f3413452cae38dd41689a6bb1 |
| institution | Directory Open Access Journal |
| issn | 2352-9520 |
| language | English |
| last_indexed | 2024-04-09T15:30:20Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
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| series | OpenNano |
| spelling | doaj.art-9be6db3f3413452cae38dd41689a6bb12023-04-28T08:55:50ZengElsevierOpenNano2352-95202023-05-0111100142Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticlesMohammed Numan Alamassi0Suet Lin Chia1Che Azurahanim Che Abdullah2Mas Jaffri Masarudin3Department of Cell and Molecular Biology Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, UPM Selangor 43400, MalaysiaDepartment of Microbiology Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, UPM Selangor 43400, Malaysia; UPM-MAKNA Cancer Research Laboratory Institute of Bioscience, Universiti Putra Malaysia, Serdang, UPM Selangor 43400, MalaysiaMaterial Synthesis and Characterization Laboratory, Institute of Nanoscience and Nanotechnology, Universiti Putra Malaysia, MalaysiaDepartment of Cell and Molecular Biology Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, UPM Selangor 43400, Malaysia; UPM-MAKNA Cancer Research Laboratory Institute of Bioscience, Universiti Putra Malaysia, Serdang, UPM Selangor 43400, Malaysia; Material Synthesis and Characterization Laboratory Institute of Advanced Technology, Universiti Putra Malaysia, Malaysia; Corresponding author at: Department of Cell and Molecular Biology Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, UPM Selangor 43400, Malaysia.Conventional anti-cancer drugs, including doxorubicin, are associated with high toxicity and non-specific distribution in the body which results in a cascade of side effects. Cancer cells can utilize autophagy to promote tolerance to the stress induced by anti-cancer agents; this may be the major cause of drug resistance in advanced tumors. Owing to the molecular dynamism of cancer cells, targeting the pro-apoptotic survival pathways such as autophagy may increase the effectiveness of existing therapeutic agents at lower concentrations, thereby reducing the side effects of such agents. SAR405 is an inhibitor of autophagy activity due to its molecular interactions within the ATP binding site; however, it suffers from extracellular premature degradation and poor cellular uptake. Conversely, chitosan nanoparticles are considered biologically degradable, non-toxic, and biocompatible drug delivery agents that can be used to minimize the side effects of conventional therapeutic agents whilst increasing their intracellular uptake. In this study, a binary therapeutic strategy for the enhancement of the efficacy of doxorubicin while simultaneously inhibiting autophagy via a nano-mediated delivery system is reported. Autophagic inhibition was achieved via the improvement of SAR405 cellular uptake using SAR405-loaded chitosan nanoparticles. The synthesized nanoparticles were subsequently characterized for parameters of hydrodynamic diameter and polydispersity, while encapsulation and drug loading efficiencies were determined. Morphological characterization of the nanoparticles was elucidated using electron microscopy, and the cytotoxicity of the SAR405-loaded chitosan nanoparticles in combination treatments with doxorubicin was assessed through MTT and Annexin-v apoptosis assays. Autophagy progression through autophagosome formation was also evaluated using CYTO-ID staining. Following encapsulation, the size of the SAR405-loaded chitosan nanoparticles significantly increased from 54 nm to 161 nm at 10 µM SAR405 concentration, while the polydispersity index increased from 0.11 to 0.31 denoting presence of both encapsulated and unencapsulated moieties. When A549 lung cancer cells were treated with the IC50 values of doxorubicin in combination with SAR405-encapsulated CNP, an approximately 47% more reduction in cell viability was observed via the Annexin V-FITC/PI assay compared to using doxorubicin alone. Inhibition of autophagy was also detected in cells treated with SAR405 delivered using the nanoparticle system and was thought to be the primary reason towards a decrease in the resistance of the cancer cells to doxorubicin and thus increased its efficacy at lower concentrations. Therefore, this study has demonstrated a potential way of targeting cancer cell survival pathways that can be considered an effective way of increasing the efficacy of chemotherapeutic drugs.http://www.sciencedirect.com/science/article/pii/S235295202300021XDoxorubicinSar405Chitosan nanoparticlesNanomedicineNanotechnologyAutophagy |
| spellingShingle | Mohammed Numan Alamassi Suet Lin Chia Che Azurahanim Che Abdullah Mas Jaffri Masarudin Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticles OpenNano Doxorubicin Sar405 Chitosan nanoparticles Nanomedicine Nanotechnology Autophagy |
| title | Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticles |
| title_full | Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticles |
| title_fullStr | Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticles |
| title_full_unstemmed | Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticles |
| title_short | Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticles |
| title_sort | increased efficacy of biologics following inhibition of autophagy in a549 lung cancer cells in bimodal treatment of doxorubicin and sar405 loaded chitosan nanoparticles |
| topic | Doxorubicin Sar405 Chitosan nanoparticles Nanomedicine Nanotechnology Autophagy |
| url | http://www.sciencedirect.com/science/article/pii/S235295202300021X |
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