Chen Haifang, Li Guofeng, Liu Ye, Lang Yifan, Yang Wuliang, Zhang Wugang, Liang Xinli
Jiangxi University of Chinese Medicine, Nanchang, China.
Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang, China.
Front Pharmacol. 2022 Feb 25;13:827520. doi: 10.3389/fphar.2022.827520. eCollection 2022.
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 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.
紫杉醇（PTX）一直是肺癌的一线治疗药物；然而，由于多药耐药性（MDR）和不良反应，其临床应用受到限制。因此，迫切需要探索能够通过降低耐药性和不良反应来增强PTX抗癌疗效的药物。桔梗汤（JG）在肺癌治疗中用作引经药和佐药。然而，其佐药作用机制尚不清楚。本研究的目的是确定JG是否能增强PTX的抗癌作用。采用高效液相色谱-串联质谱法（HPLC-MS/MS）检测PTX的组织分布。基于体重和肿瘤抑制率，评估PTX与JG联合用药对Lewis肺癌C57BL/6J小鼠的抗肺癌作用。采用HPLC-MS和成像技术测定肿瘤组织中的PTX浓度。使用生化分析仪和酶联免疫吸附测定法（ELISA）检测生化指标。基于细胞增殖、膜联蛋白V-异硫氰酸荧光素（Annexin V-FITC）凋亡检测和蛋白质印迹法，阐明PTX-JG组合在A549/PTX细胞中的抗癌机制。组织分布分析表明，给予PTX与JG联合用药后，PTX在肺、肝和心脏中的分布增加。JG通过增加红细胞和血小板计数；提高血红蛋白、白细胞介素（IL）-2和肿瘤坏死因子-α水平；增加CD4+T细胞和CD4+/CD8+比值；以及降低IL-10水平，显著增强了PTX的抗癌作用。给予JG导致PTX在肿瘤病变部位的分布增加，并且还通过抑制肿瘤细胞增殖和促进凋亡增强了PTX的抗癌作用。此外，JG通过抑制肺耐药相关蛋白、多药耐药蛋白1、P-糖蛋白和乳腺癌耐药蛋白的表达来逆转PTX耐药性。此外，JG与PTX的组合降低了丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平，并且不影响肌酸激酶同工酶MB水平。因此，我们的发现表明JG通过下调MDR相关蛋白增强了PTX的抗癌作用，并显示出免疫协同增强作用。因此，PTX与JG的组合因其协同和解毒作用在肺癌治疗中显示出潜力。
