Abstract
Paclitaxel (PTX) has been the first-line treatment for lung cancer; however, its clinical use is limited due to multidrug resistance (MDR) and adverse effects. Thus, there is an urgent need to explore agents that can enhance the anticancer efficacy of PTX by reducing drug resistance and adverse reactions. Jiegeng decoction (JG) was used as the meridian guide drug and adjuvant drug in treatment of lung cancer. However, the mechanism of adjuvant effect was unclear. The aim of this study was to determine whether JG could potentiate the anticancer effect of PTX. Tissue distribution of PTX was detected using HPLC-MS/MS. The anti-lung cancer effect of the combination of PTX and JG in Lewis lung cancer C57BL/6J mice was evaluated based on the body weight and tumor-inhibition rate. PTX concentration in tumors was determined using HPLC-MS and in vivo imaging. Biochemical indices were detected using biochemical analyzer and ELISA. The anticancer mechanism of the PTX-JG combination in A549/PTX cells was elucidated based on cell proliferation, annexin V-FITC apoptosis assay, and western blotting. Tissue distribution analysis showed that the distribution of PTX increased in the lungs, liver, and heart upon administering the combination of PTX and JG. JG remarkably enhanced the anticancer effect of PTX by increasing the red blood cell and platelet counts; increasing hemoglobin, interleukin (IL)-2, and tumor necrosis factor-α levels; increasing CD4+T cells and the CD4+/CD8+ ratio; and decreasing IL-10 levels. JG administration led to the increased distribution of PTX at the tumor lesion sites and also potentiated the anticancer effect of PTX by inhibiting tumor cell proliferation and promoting apoptosis. Moreover, JG reversed PTX resistance by inhibiting the expression of lung resistance-related proteins, multiresistance protein 1, P-glycoprotein, and breast cancer-resistant protein. Furthermore, the combination of JG and PTX decreased alanine aminotransferase and aspartate aminotransferase levels and did not affect creatine kinase-MB levels. Therefore, our discovery suggests that JG increased the anticancer effect of PTX by downregulating the MDR-related protein and demonstrated a synergistic enhancement of immunity. Thus, the combination of PTX with JG shows potential in the management of lung cancer owing to its synergistic and detoxifying effects.
Highlights
Lung cancer remains the leading cause of cancer deaths and has a high incidence (Bade and Cruz, 2020; Yang et al, 2020)
The RSD for interday and intraday precision was less than 12.2%, the accuracy bias was −10.26–11.69%, and the RSD for stability was less than 13.58%
Our findings found that Jiegeng decoction (JG) alone could significantly decrease the expression of these efflux transporters, which suggested that JG, as a meridian guide drug, has a regulatory effect on drug-resistant proteins and is consistent with published findings of meridian guide drugs
Summary
Lung cancer remains the leading cause of cancer deaths and has a high incidence (Bade and Cruz, 2020; Yang et al, 2020). Several derivatives of PTX and different drug dosages have been tested, which have resulted in minimal side effects due to an increase in drug concentration in the target area and a decrease in nonspecific distribution (Li et al, 2021; Urbanik et al, 2021). The main cause of MDR during chemotherapy is closely related to MDR-related transporters, which mainly include P-glycoprotein (P-gp/ABCB1/MDR1), breast cancer-resistant protein (BCRP/ABCG2), multiresistance protein 1 (MRP1/ ABCC1), and lung resistance-related protein (MVP/LRP) (Mohammad et al, 2018). These efflux proteins are widely distributed in the small intestine, liver, kidneys, and other tissues, and are highly expressed especially in tumor sites. Several research groups are focusing on developing downregulators of drug-resistant proteins, which could sensitize chemotherapeutic drugs when used for cancer treatment (Chang et al, 2020; Eid et al, 2020)
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