Evaluation of a Novel PLGA-HA-Based Drug Delivery System Targeting the cell cycle and PI3K/AKT/mTOR Pathway in HCT116 Colorectal Carcinoma Cells with Differing P53 Statuses

Dlshad H. Hassan; Goran  Othman; Esmaeil  Babaei

doi:10.21271/ZJPAS.36.6.1

Authors

Dlshad H. Hassan Department of Biology, Faculty of Science, Soran University, Soran-Erbil, Iraq
Goran Othman 1Department of Medical Laboratory Technology, Erbil Health and Medical Technical College, Erbil Polytechnic University, Kirkuk St., Erbil 44001, Kurdistan Region, Iraq. 2Department of Medical Laboratory Technology, Al-Qalam University College, Kirkuk 36001, Iraq.
Esmaeil Babaei Department of Biology, School of Natural Sciences, University of Tabriz, Tabriz, Iran

DOI:

https://doi.org/10.21271/ZJPAS.36.6.1

Keywords:

PLGA,, hyaluronic acid, colorectal carcinoma, drug delivery system, PLG PI3K/AKT/mTOR pathway

Abstract

Colorectal carcinoma (CRC) is a very important health problem all over the world, and the P53 gene plays an important role in tumor development and in treatment response. The strategy of developing novel DDS that could target specific tumor pathways is one of the most promising approaches to improve therapeutic efficacy. The aim of this study was to evaluate the performance of a newly synthesized PLGA-HA-based DDS encapsulating the mTOR inhibitor Dactolisib on HCT116 CRC cells with differing P53 statuses; P53 positive and P53 negative. The previously synthesized and characterized DDS was tested on HCT-116 P53 positive and negative cell lines. Assessments included: cell cycle distribution analysis by flow cytometry; gene expression profiling of key components of the PI3K/AKT/mTOR pathway by using qPCR, and proteomic via Western blotting. DDS induced a differential effect on the cell cycle progress, which arrested the cell cycle at the G0/G1 phase in a statistically significant way in P53 positive cells, while in P53 negative cells, it resulted in an increase in the S phase. The gene expression analysis revealed downregulation of PIK3CA, AKT1, and MTOR in both cell lines; however, the inhibition seemed more potent in P53-positive cells. The proteomic analysis confirmed reduced p-AKT and p-mTOR with increased levels of P53 protein in P53-positive cells. The new PLGA-HA-based DDS exhibits promising anti-cancer activity against CRC cells, which have different influences related to P53 status. These observations suggest an application for personalized cancer therapy, particularly in the case of tumors with functional P53.

References

BABAMOHAMADI, M., BABAEI, E., AHMED SALIH, B., BABAMOHAMMADI, M., JALAL AZEEZ, H. & OTHMAN, G. J. F. I. M. B. 2022. Recent findings on the role of wild-type and mutant p53 in cancer development and therapy. 9, 903075.

DLSHAD H. HASSAN, G. O., ESMAEIL BABAEI 2024. Synthesis And Characterization Of Novel PLGA And HA-Based Nanoparticle Drug Delivery System Incorporating Dactolisib And ItsIn VitroEvaluation Against HCT116 Colorectal Carcinoma Cells. African Journal of Biomedical Research, 27, 1178-1183.

DOWLING, R. J., TOPISIROVIC, I., FONSECA, B. D., SONENBERG, N. J. B. E. B. A.-P. & PROTEOMICS 2010. Dissecting the role of mTOR: lessons from mTOR inhibitors. 1804, 433-439.

EASTMAN, A. J. J. O. C. B. 2004. Cell cycle checkpoints and their impact on anticancer therapeutic strategies. 91, 223-231.

GLAVIANO, A., FOO, A. S., LAM, H. Y., YAP, K. C., JACOT, W., JONES, R. H., ENG, H., NAIR, M. G., MAKVANDI, P. & GEOERGER, B. J. M. C. 2023. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. 22, 138.

HOU, X., ZHONG, D., CHEN, H., GU, Z., GONG, Q., MA, X., ZHANG, H., ZHU, H. & LUO, K. J. C. P. 2022. Recent advances in hyaluronic acid-based nanomedicines: Preparation and application in cancer therapy. 292, 119662.

KUMAR, A., GAUTAM, V., SANDHU, A., RAWAT, K., SHARMA, A. & SAHA, L. J. W. J. O. G. S. 2023. Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review. 15, 495.

LEIPHRAKPAM, P. D. & ARE, C. J. I. J. O. M. S. 2024. PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment. 25, 3178.

LI, X., LIU, J., CHEN, H., CHEN, Y., WANG, Y., ZHANG, C. Y. & XING, X.-H. J. G. C. E. 2023. Multi-functional engineered polypeptide-based drug delivery systems for improved cancer therapy. 4, 173-188.

LU, Y., CHENG, D., NIU, B., WANG, X., WU, X. & WANG, A. J. P. 2023. Properties of poly (lactic-co-glycolic acid) and progress of poly (lactic-co-glycolic acid)-based biodegradable materials in biomedical research. 16, 454.

MAREI, H. E., ALTHANI, A., AFIFI, N., HASAN, A., CACECI, T., POZZOLI, G., MORRIONE, A., GIORDANO, A. & CENCIARELLI, C. J. C. C. I. 2021. p53 signaling in cancer progression and therapy. 21, 703.

MICHEL, M., KAPS, L., MADERER, A., GALLE, P. R. & MOEHLER, M. J. C. 2021. The role of p53 dysfunction in colorectal cancer and its implication for therapy. 13, 2296.

MUNRO, A., LAIN, S. & LANE, D. J. B. J. O. C. 2005. P53 abnormalities and outcomes in colorectal cancer: a systematic review. 92, 434-444.

PATRA, D., BHAVYA, K., RAMPRASAD, P., KALIA, M., PAL, D. J. A. I. P. C. & BIOLOGY, S. 2023. Anti-cancer drug molecules targeting cancer cell cycle and proliferation. 135, 343-395.

PENG, Y., WANG, Y., ZHOU, C., MEI, W. & ZENG, C. J. F. I. O. 2022. PI3K/Akt/mTOR pathway and its role in cancer therapeutics: are we making headway? 12, 819128.

RASCIO, F., SPADACCINO, F., ROCCHETTI, M. T., CASTELLANO, G., STALLONE, G., NETTI, G. S. & RANIERI, E. J. C. 2021. The pathogenic role of PI3K/AKT pathway in cancer onset and drug resistance: an updated review. 13, 3949.

SIEGEL, R. L., WAGLE, N. S., CERCEK, A., SMITH, R. A. & JEMAL, A. J. C. A. C. J. F. C. 2023. Colorectal cancer statistics, 2023. 73, 233-254.

SIRICO, M., D’ANGELO, A., GIANNI, C., CASADEI, C., MERLONI, F. & DE GIORGI, U. J. C. 2023. Current state and future challenges for PI3K inhibitors in cancer therapy. 15, 703.

THOREEN, C. C., CHANTRANUPONG, L., KEYS, H. R., WANG, T., GRAY, N. S. & SABATINI, D. M. J. N. 2012. A unifying model for mTORC1-mediated regulation of mRNA translation. 485, 109-113.

TOSON, B., FORTES, I. S., ROESLER, R. & ANDRADE, S. F. J. P. R. 2022. Targeting Akt/PKB in pediatric tumors: A review from preclinical to clinical trials. 183, 106403.

YAKKALA, P. A., NAAZ, F., SHAFI, S. & KAMAL, A. J. E. O. O. T. T. 2024. PI3K and tankyrase inhibitors as therapeutic targets in colorectal cancer. 28, 159-177.

YOON, M.-S. J. I. J. O. N. 2020. Nanotechnology-based targeting of mTOR signaling in cancer. 5767-5781.

ZOU, Z., TAO, T., LI, H., ZHU, X. J. C. & BIOSCIENCE 2020. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. 10, 31.