Effects of increased accumulation of doxorubicin due to emodin on efflux transporter and LRP1 expression in lung adenocarcinoma and colorectal carcinoma cells

Abstract

Treatment with doxorubicin (dox) and emodin, separately and together, under normoxic and hypoxia-like conditions induced by CoCl, led to greater intracellular compound accumulation over 10 h post-addition in the presence of CoCl in lung adenocarcinoma (A549) and colorectal carcinoma (HCT-15) cell lines. Confocal microscopy revealed that emodin, by itself, showed high cytosolic distribution in both cell lines, at 40 min post-addition but had entered the nuclei by 2 h, while dox entered the nuclei by 40 min. Both compounds modulated the expression of the efflux transporters (PgP, ABCG2, or MRP1-4) and the endocytic receptor, low-density lipoprotein receptor-related protein 1 (LRP1), to different extents under the study conditions. Efflux transporter upregulation was linked to lower intracellular compound levels due to greater efflux. Increased dox accumulation was accompanied by unaltered expression or upregulation of LRP1 in A549 cells. In both cell lines, increased accumulation of dox and emodin was observed whenever LRP1 and the efflux transporters known to transport dox and emodin were all up- or downregulated concomitantly. Increased growth inhibition was linked to co-treatment with dox and emodin and with increased ligand accumulation. The results presented in this study raise the hypothesis that higher production of LRP1 protein may be associated with higher endocytosis of upregulated transporter proteins at the cell surface, and hence, increased dox and emodin accumulation and growth inhibition. If so, elevation of LRP1 expression may be a useful target for interventions to promote the efficacy of these and other anticancer drugs.

Emodin enhances cisplatin sensitivity in non-small cell lung cancer through Pgp downregulation

“…Previous studies have demonstrated that emodin and cisplatin alone or in combination can significantly decrease the expression of Pgp and MRP1 in bladder cancer cells (32,35,39). Furthermore, emodin and doxorubicin significantly decrease the expression of Pgp and MRP1 in colon cancer cells (39). In the present study, the effect of emodin on the expression of Pgp and MRP1 in A549 and H460 cells was investigated.…”

“…In particular, the drug protein pump mediated by Pgp, MRP and other drug resistance-related proteins, such as BCRP and LRP1, is the main mechanism by which tumors develop MDR (27). Previous studies have demonstrated that emodin and cisplatin alone or in combination can significantly decrease the expression of Pgp and MRP1 in bladder cancer cells (32,35,39). Furthermore, emodin and doxorubicin significantly decrease the expression of Pgp and MRP1 in colon cancer cells (39).…”

Connecting Cholesterol Efflux Factors to Lung Cancer Biology and Therapeutics

“…A higher level of LRP1 protein may be associated with a higher endocytosis of upregulated transporter proteins at the cell surface, which is likely the cause of increased doxorubicin and emodin (an anti-inflammatory agent) accumulation and growth inhibition in lung adenocarcinoma and colorectal carcinoma cells [62]. Additionally, emodin was shown to upregulate LRP1 in a prostate cancer cell as well as nonprostate cell lines A549 (lung), HCT-15 (colon) and MG-63 (bone) under normoxic and hypoxia-like conditions via reactive oxygen species (ROS) generation [63].…”

“…Additionally, emodin was shown to upregulate LRP1 in a prostate cancer cell as well as nonprostate cell lines A549 (lung), HCT-15 (colon) and MG-63 (bone) under normoxic and hypoxia-like conditions via reactive oxygen species (ROS) generation [63]. Therefore, LRP1 expression may be a point for interventions to promote efficacy of anticancer drugs by allowing their more efficient uptake in lung adenocarcinoma and colorectal carcinoma [62,63].…”

Progress on the Study of the Anti-Tumor Effect of Emodin

“…In addition to the direct role of emodin in the treatment of lung cancer, it can also play a good indirect role in the treatment of lung cancer. Emodin has been found to have a significant synergistic effect when used in combination with some drugs for lung cancer that do not work well because of new drug resistance [35] [36].…”