Paclitaxel and Sorafenib: The Effective Combination of Suppressing the Self-Renewal of Cancer Stem Cells

Abstract

“Combination therapy”, which is a treatment modality combining two or more therapeutic agents, is considered a cornerstone of cancer therapy. The combination of anticancer drugs, of which functions are different from the other, enhances the efficiency compared to the monotherapy because it targets cancer cells in a synergistic or an additive manner. In this study, the combination of paclitaxel and sorafenib in low concentration was evaluated to target cancer stem cells, miPS-BT549cmP and miPS-Huh7cmP cells, developed from mouse induced pluripotent stem cells. The synergistic effect of paclitaxel and sorafenib on cancer stem cells was assessed by the inhibition of proliferation, self-renewal, colony formation, and differentiation. While the IC50 values of paclitaxel and sorafenib were approximately ranging between 250 and 300 nM and between 6.5 and 8 µM, respectively, IC50 of paclitaxel reduced to 20 and 25 nM, which was not toxic in a single dose, in the presence of 1 µM sorafenib, which was not toxic to the cells. Then, the synergistic effect was further assessed for the potential of self-renewal of cancer stem cells by sphere formation ability. As a result, 1 µM of sorafenib significantly enhanced the effect of paclitaxel to suppress the number of spheres. Simultaneously, paclitaxel ranging in 1 to 4 nM significantly suppressed not only the colony formation but also the tube formation of the cancer stem cells in the presence of 1 µM sorafenib. These results suggest the combination therapy of paclitaxel and sorafenib in low doses should be an attractive approach to target cancer stem cells with fewer side effects.

Paclitaxel-Based Chemotherapy Targeting Cancer Stem Cells from Mono- to Combination Therapy

“…In this study, the Sor–PTX combination in low concentrations was evaluated to target CSCs, and significant suppression of the CSCs’ properties was found. These results pose a novel approach for targeting CSCs with anticancer drugs in low doses, which could effectively reduce the toxic side effects of chemotherapy [ 137 ].…”

Oxidative Stress Activated by Sorafenib Alters the Temozolomide Sensitivity of Human Glioma Cells Through Autophagy and JAK2/STAT3-AIF Axis

“…Because sorafenib can induce autophagy in tumors ( Nawara et al, 2020 ) and STAT3 is associated with autophagy, we investigated the changes in autophagy induced by the combination of sorafenib and TMZ. As shown in Figure 6A and Supplementary Figure 6A , LC3-II expression showed a greater increase in U251 cells treated with the combination of sorafenib and TMZ than in cells treated with either agent alone.…”

“…Sorafenib is a novel diaryl urea compound and multikinase inhibitor that specifically reduces the activity of Raf kinase ( Hung et al, 2014 ). In addition, studies have observed a synergistic antitumor effect between sorafenib and conventional chemotherapy drugs in cancer, such as pancreatic cancer ( Booth et al, 2020 ), and in cancer stem cells ( Nawara et al, 2020 ). Moreover, sorafenib has the ability to effectively cross the blood-brain barrier and sorafenib treatment is well-tolerated by patients ( Siegelin et al, 2010 ).…”

Current Perspectives on Taxanes: Focus on Their Bioactivity, Delivery and Combination Therapy

“…Sorafenib was approved as a first-line treatment for advanced renal cell carcinoma (2005), unresectable hepatocellular carcinoma (2007), and metastatic differentiated thyroid cancer (2013) [ 175 ]. Nawara et al [ 176 ] confirmed that a combination of sorafenib and paclitaxel at nontoxic concentrations of these drugs had substantially suppressed the oncogenic action of CSCs and, thereby, tumorigenesis progression. Such an approach could be beneficial in terms of reducing the side effects of common anticancer therapy.…”