Propofol Augments Paclitaxel-Induced Cervical Cancer Cell Ferroptosis In Vitro

Abstract

Introduction: Cervical cancer is common in women. The present standardized therapies including surgery, chemotherapy, and radiotherapy are still not enough for treatment. Propofol is the most commonly used intravenous anesthetic agent for induction and maintenance of anesthesia and has been shown to exert anti-malignancy effects on cancer cells, inducing oxidative stress and apoptosis. However, the biological effects of propofol have not yet been systematically assessed. In this study, we examined the ferroptosis-related changes caused by propofol and the chemotherapeutic agent paclitaxel besides apoptosis in vitro.Methods: Cervical cancer cell lines (C-33A and HeLa) were treated with propofol alone (1, 2, 5, 10, and 20 μg/ml) or in combination with paclitaxel (0.5, 1, and 5 μg/ml). The viability was assessed using cell counting kit-8 (CCK8), apoptosis was detected by flow cytometry, morphological changes of mitochondria were examined using transmission electron microscope (TEM), cellular reactive oxygen species (ROS), and intracellular ferrous ions were determined by fluorescence microscope or confocal microscopy. The expression and cellular localization of apoptosis and ferroptosis-related molecules were detected by Western blot and multiplex immunohistochemistry (mIHC), respectively. Calcusyn software was used to determine whether propofol has a synergistic effect with paclitaxel.Results: Propofol and paclitaxel inhibited C-33A and HeLa cell viability. There were also synergistic effects when propofol and paclitaxel were used in combination at certain concentrations. In addition, propofol promoted paclitaxel-induced cervical cancer cell death via apoptosis. ROS level and Fe2+ concentrations were also influenced by different drug treatments. Furthermore, propofol, propofol injectable emulsion, and paclitaxel induced ferroptosis-related morphological changes of mitochondria in C-33A and HeLa cells. Ferroptosis-related signaling pathways including SLC7A11/GPX4, ubiquinol/CoQ10/FSP1, and YAP/ACSL4/TFRC were found to be changed under drug treatments.Conclusion: Propofol showed synergistic anticancer effects with paclitaxel in cervical cancer cells. Propofol and paclitaxel may induce ferroptosis of cervical cancer cells besides apoptosis.

ACSL4 as a Potential Target and Biomarker for Anticancer: From Molecular Mechanisms to Clinical Therapeutics

“… Ou et al (2022) found circular RNA (CircLMO1) could inhibit cervical cancer proliferation by activating ACSL4-induced ferroptosis, and could be a promising anti-cancer biomarker for cervical cancer. As for chemotherapy treatment of cervical cancer, ACSL4-mediated ferroptosis could play an important role in propofol synergistic anticancer effects with paclitaxel ( Zhao et al, 2022 ).…”

The effect of narcotics on ferroptosis-related molecular mechanisms and signalling pathways

“…However, animal experiments and in vitro cell experiments consistently show that propofol has the potential to inhibit the malignancy of primary cancers (Sessler and Riedel, 2019), promoting ferroptosis in cancer cells. Clinically relevant concentrations (5 µg/ml, 10 µg/ml, 20 µg/ ml) of propofol can inhibit the viability of cervical cancer cells in vitro and enhance the morphological changes related to ferroptosis and mitochondrial atrophy in HeLa cells induced by paclitaxel (Zhao et al, 2022). It is manifests as increased intracellular Fe 2+ concentrations, inhibition of the SLC7A11/GPX4 and ubiquinol/FSP1/CoQ10 pathways, upregulation of the expression of the ferroptosis regulators ACSL4, TFRC, etc., to promote ferroptosis in C-33A and HeLa cells.…”

“…Furthermore, morphological features such as intense membrane blebbing and loss of plasma membrane integrity in pyroptosis and double-membrane wrapping, autophagolysosome formation from autophagic cells were not observed in ferroptotic cells ( Liang et al, 2019 ). The only unique morphological features of ferroptosis are mitochondrial shrinkage, reduction or disappearance of mitochondrial cristae, and increased bilayer density ( Yagoda et al, 2007 ; Zhao et al, 2022 ). Although different types of mechanisms regulating cell death have different morphological and biochemical characteristics, there is still some interference between regulators and the components of these different processes.…”

The Role of Ferroptosis-Related Molecules and Significance of Ferroptosis Score in Cervical Cancer

“…Several studies have indicated the potential use of ferroptosis inducers to trigger ferroptosis for cancer therapy, especially for aggressive tumors that are resistant to conventional therapies [11][12][13]. For instance, propofol may be a potential adjuvant to enhance the chemotherapy sensitivity of CC cells via activating ferroptosis [14]. In addition, Roh et al revealed that ferroptosis inducers can also act synergistically with some conventional drugs, such as cisplatin, to inhibit tumor growth in a mouse model of head and neck cancer [15].…”