Qing-Kai-Ling Injection Acts Better Than Shen-Fu Injection in Enhancing the Antitumor Effect of Gefitinib in Resistant Non-Small Cell Lung Cancer Models

Ya-Ya Yu; Yan-Juan Zhu; Ying Zou; Zhen-Zhen Xiao; Shuai Shi; Yi-Hong Liu; Xue-Song Chang; Ya-Dong Chen; Hai-Bo Zhang

doi:10.1155/2021/9911935

Qing-Kai-Ling Injection Acts Better Than Shen-Fu Injection in Enhancing the Antitumor Effect of Gefitinib in Resistant Non-Small Cell Lung Cancer Models

Evid Based Complement Alternat Med. 2021 Oct 4:2021:9911935. doi: 10.1155/2021/9911935. eCollection 2021.

Authors

Ya-Ya Yu^{1

2}, Yan-Juan Zhu^{1

2

3

4}, Ying Zou^{1

5}, Zhen-Zhen Xiao^{1

2}, Shuai Shi^{1

6}, Yi-Hong Liu^{1

2}, Xue-Song Chang^{1

2}, Ya-Dong Chen^{1

2}, Hai-Bo Zhang^{1

2

3

4

7}

Affiliations

¹ Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
² Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
³ Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China.
⁴ Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China.
⁵ Department of Integrated Traditional and Western Medicine, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
⁶ Department of Respiration Medicine, Luoyang First People's Hospital, Luoyang, Henan, China.
⁷ State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, China.

Abstract

Patients with EGFR gene mutation often obtain de novo resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or develop secondary resistance to EGFR-TKIs after taking EGFR-TKI therapy. Traditional Chinese medicine (TCM) with different treatment principles, in combination with EGFR-TKIs, plays an important role in the treatment of cancers including resistant non-small cell lung cancer (NSCLC). However, inappropriate use of TCM herbs may induce resistance to gefitinib. Therefore, it is of a great value to evaluate which TCM treatment principle should be combined with EGFR-TKIs, and which one should be avoided, and find out the potential mechanisms. The lentiviral transfection assay was used for overexpression of PIK3CA mutation gene in PC-9 cells to construct PC-9-PIK3CA-mutation (PC-9-PIK3CA-M) cells. Cell proliferation, apoptosis, and the expression of EGFR/PI3K/AKT and EGFR/RAS/RAF/ERK in PC-9-PIK3CA-M and H1975 cells treated by the typical cooling-heat drug, Qing-kai-ling (QKL) and Tan-re-qing (TRQ), or the typical warming-yang drug, Shen-fu (SF) and gefitinib treatment, were detected by MTT, Annexin V/PI double labeling, and Western blot assays, respectively. Tumor xenograft and immunohistochemistry experiments were carried out to confirm the in vitro findings. PC-9-PIK3CA-M cells were less sensitive to gefitinib, when compared with PC-9 cells. QKL injection and TRQ injection, not SF injection, combined with gefitinib induced significantly increased cell growth inhibition and apoptosis in PC-9-PIK3CA-M and H1975 cells. SF injection antagonized the effect of gefitinib in promoting cancer cell apoptosis. QKL injection and TRQ injection increased the sensitivity of gefitinib by inhibiting the phosphorylation of AKT or ERK in H1975 and PC-9-PIK3CA-M cells. Similar findings were observed in vivo in H1975 xenograft mouse model. QKL and TRQ, with cooling-heat TCM treatment principle, should be combined with gefitinib in the treatment of NSCLC. Furthermore, warming-yang drug SF should be avoided to be used together with EGFR-TKIs.