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Nanoencapsulation of Docetaxel Induces Concurrent Apoptosis and Necroptosis in Human Oral Cancer Cells (SCC-9) via

Parul Gupta¹, Arpita Singh², Ajay Kumar Verma¹

¹Department of Respiratory Medicine, King George's Medical University, Lucknow, Uttar Pradesh 226003 India.

Indian Journal of Clinical Biochemistry : IJCB

|May 26, 2023

Abstract:

Human oral squamous cell carcinoma is the sixth most frequent malignant cancer, with an unacceptably high death rate that affects people's health. Albeit, there are several clinical approaches for diagnosing and treating oral cancer they are still far from ideal. We previously synthesised and characterised the docetaxel nanoformulation (PLGA-Dtx) and discovered that docetaxel nanoencapsulation may suppress oral cancer cells. The goal of this study was to figure out the mechanism involved in the suppression of oral cancer cell proliferation. We discovered that PLGA-Dtx inhibited SCC-9 cell growth considerably as compared to free docetaxel (Dtx), and that the viability of SCC-9 cells treated with PLGA-Dtx was decreased dose-dependently. MTT assay showed that PLGA-Dtx selectively inhibited the growth of PBMCs from oral cancer patients while sparing PBMCs from normal healthy controls. Further, flow cytometry analysis showed that PLGA-Dtx induced apoptosis and necroptosis in SCC-9 cells. G2/M cell cycle arrest has been confirmed on exposure of PLGA-Dtx for 24 h in SCC-9 cells. Interestingly, western blot investigation found that PLGA-Dtx increased the amounts of necroptic proteins and apoptosis-related proteins more efficiently than Dtx. Furthermore, PLGA-Dtx was more effective in terms of ROS generation, and mitochondrial membrane potential depletion. Pretreatment with necroptosis inhibitor Nec-1 efficiently reversed the ROS production and further recover MMP caused by PLGA-Dtx. Overall, this study revealed a mechanistic model of therapeutic response for PLGA-Dtx in SCC-9 cells and proposed its potency by inducing cell death via activation of concurrent apoptosis and necroptosis in SCC-9 cells via TNF-α/RIP1/RIP3 and caspase-dependent pathway.

Insights

Docetaxel nanoformulation (PLGA-Dtx) effectively suppresses oral cancer cells by inducing apoptosis and necroptosis. This targeted therapy shows promise for treating oral squamous cell carcinoma, offering a new therapeutic strategy.

Area of Science:

Oncology
Nanomedicine
Cell Biology

Background:

Oral squamous cell carcinoma is a prevalent cancer with a high mortality rate.
Current diagnostic and treatment methods for oral cancer are suboptimal.
Docetaxel nanoformulation (PLGA-Dtx) was previously synthesized and shown to suppress oral cancer cells.

Purpose of the Study:

To elucidate the mechanism by which PLGA-Dtx suppresses oral cancer cell proliferation.
To investigate the selective toxicity of PLGA-Dtx against cancer cells.

Main Methods:

Cell viability assays (MTT) to assess growth inhibition.
Flow cytometry to analyze apoptosis and necroptosis induction.
Western blot to examine protein expression.
Analysis of reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP).

Main Results:

PLGA-Dtx significantly inhibited SCC-9 cell growth and viability in a dose-dependent manner, outperforming free docetaxel.
PLGA-Dtx selectively inhibited peripheral blood mononuclear cells (PBMCs) from oral cancer patients while sparing those from healthy controls.
PLGA-Dtx induced both apoptosis and necroptosis in SCC-9 cells, leading to G2/M cell cycle arrest.
PLGA-Dtx enhanced ROS generation and depleted MMP, effects partially reversed by necroptosis inhibition.

Conclusions:

PLGA-Dtx demonstrates potent therapeutic effects against oral squamous cell carcinoma cells.
The mechanism involves the induction of concurrent apoptosis and necroptosis via the TNF-α/RIP1/RIP3 and caspase-dependent pathways.
PLGA-Dtx represents a promising targeted therapy for oral cancer, warranting further clinical investigation.

Read full analysis

Keywords:

Apoptosis Mitochondrial membrane potential Oral cancer Reactive oxygen species

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