Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways

Abstract

Multidrug resistance (MDR) is considered to be the major contributor to failure of chemotherapy in oral squamous cell carcinoma (SCC). This study was aimed to explore the effects and mechanisms of glaucarubinone (GLU), one of the major quassinoids from Simarouba glauca DC, in potentiating cytotoxicity of paclitaxel (PTX), an anticancer drug in KB cells. Our data showed that the administration of GLU pre-treatment significantly enhanced PTX anti-proliferative effect in ABCB1 over-expressing KB cells. The Rh 123 drug efflux studies revealed that there was a significant transport function inhibition by GLU-PTX treatment. Interestingly, it was also found that this enhanced anticancer efficacy of GLU was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Further, the combined treatment of GLU-PTX had significant decrease in the expression levels of P-gp, MRPs, and BCRP in resistant KB cells at both mRNA and protein levels. Furthermore, the combination treatments showed significant reactive oxygen species (ROS) production, chromatin condensation and reduced mitochondrial membrane potential in resistant KB cells. The results from DNA fragmentation analysis also demonstrated the GLU induced apoptosis in KB cells and its synergy with PTX. Importantly, GLU and/or PTX triggered apoptosis through the activation of pro-apoptotic proteins such as p53, Bax, and caspase-9. Our findings demonstrated for the first time that GLU causes cell death in human oral cancer cells via the ROS-dependent suppression of MDR transporters and p53-mediated activation of the intrinsic mitochondrial pathway of apoptosis. Additionally, the present study also focussed on investigation of the protective effect of GLU and combination drugs in human normal blood lymphocytes. Normal blood lymphocytes assay indicated that GLU is able to induce selective toxicity in cancer cells and in silico molecular docking studies support the choice of GLU as ABC inhibitor to enhance PTX efficacy. Thus, GLU has the potential to enhance the activity of PTX and hence can be a good alternate treatment strategy for the reversal of PTX resistance.

Juglone induces apoptosis of tumor stem-like cells through ROS-p38 pathway in glioblastoma

“…Therefore, many ROS-inducing agents are currently used in clinical trials for different tumors [21, 23]. These agents could not only act as direct inhibitors of cancers, but also sensitize tumor cells to chemotherapies [24]. In this study, we evaluated the growth inhibition and apoptosis induction by juglone in human GBM TSCs in vitro and in vivo, and we also confirmed that ROS was involved in juglone-induced apoptosis.…”

The Role of p21-Activated Kinases in Pancreatic Cancer

“…knockdown increased the expression of the human equilibrative nucleoside transporter 1 (hENT1), which is responsible for cellular gemcitabine uptake (158). This sensitisation may not be gemcitabine chemotherapy specific and glaucarubinone treatment and more specifically, PAK inhibition, may result in sensitisation of chemotherapy as suggested by a study where glaucaurbinone sensitised oral squamous cell carcinoma to the chemotherapy, paclitaxel (107).…”

Synthetic β‐nitrostyrene derivative CYT‐Rx20 as inhibitor of oral cancer cell proliferation and tumor growth through glutathione suppression and reactive oxygen species induction

“…Induction of apoptosis is recognized as a major anticancer mechanism for many chemotherapeutic agents, including the currently studied CYT‐Rx20 . Previous studies reported that the caspase family mediated apoptotic programmed cell death in oral cancer . Caspase‐9 is activated very early in the apoptotic cascade by cytochrome C, which is released from the mitochondria in response to apoptotic stimuli, and then downstream caspases, such as caspase‐3, are activated leading to the cleavage of key cellular proteins, such as PARP.…”