Lung cancer is the leading cause of cancer-related deaths worldwide. Almost 80% of lung cancer patients are non-small cell lung cancers (NSCLC). Cisplatin (cis-diamminedichloroplatinum (II); DDP) serves as the backbone of first-line chemotherapy for NSCLC. DDP is active for NSCLC patients with advanced-stage or early-stage that requiring adjuvant therapy. The key flaw of DDP is the development of acquired drug resistance, resulting in reduced therapeutic efficacy. Drug combination is one effective way to address this issue. However, majority of synthesized compounds failed to improve the therapeutic profile of DDP. Thus, the focus today has shifted to T̲raditional C̲hinese m̲edicine (TCM), which has been used today as a common way to improve the efficacy as well as to reduce the...[ Read more ]

Lung cancer is the leading cause of cancer-related deaths worldwide. Almost 80% of lung cancer patients are non-small cell lung cancers (NSCLC). Cisplatin (cis-diamminedichloroplatinum (II); DDP) serves as the backbone of first-line chemotherapy for NSCLC. DDP is active for NSCLC patients with advanced-stage or early-stage that requiring adjuvant therapy. The key flaw of DDP is the development of acquired drug resistance, resulting in reduced therapeutic efficacy. Drug combination is one effective way to address this issue. However, majority of synthesized compounds failed to improve the therapeutic profile of DDP. Thus, the focus today has shifted to T̲raditional C̲hinese m̲edicine (TCM), which has been used today as a common way to improve the efficacy as well as to reduce the toxicity of chemotherapy for the treatment of NSCLC.

Y̲u P̲ing F̲eng S̲an (YPFS), an ancient Chinese herbal decoction composed of A̲stragali R̲adix (AR; Huangqi), A̲tractylodis M̲acrocephalae R̲hizoma (AMR; Baizhu) and S̲aposhnikoviae R̲adix (SR; Fangfeng), has been used in the clinic for treating immune deficiency for over 800 years. In cancer therapy, YPFS is being combined with chemotherapeutic drugs to improve efficacy; however, scientific evidence to illustrate this combination effect is lacking. In order to demonstrate the anti-drug resistance of YPFS, the studies were conducted in DDP-resistant NSCLC cells (A549/DDP) both in vitro and in vivo. The application of YPFS exhibited a synergistic enhancement of DDP-induced cytotoxicity as well as of the apoptotic signalling molecules. DDP-induced expression of the multi-drug-resistance efflux transporters was markedly reduced in the presence of YPFS, resulting in a higher intracellular concentration of DDP. In addition, the application of YPFS increased DDP-induced reactive oxygen species accumulation and mitochondrial membrane potential depletion, decreased p62/TRAF6 signalling in DDP-treated A549/DDP cells. The co-treatment of DDP and YPFS in tumour-bearing nude mice reduced the tumour size robustly (by more than 80%), which was much better than the effect of DDP alone. These results indicated that YPFS could notably improve the DDP-suppressed cancer effect, which could be a consequence of elevation of intracellular DDP via drug transporters, as well as the down regulation of p62/TRAF6 signalling.

To optimize the anti-cancer function of YPFS, 14 Chinese herbal extracts having known function to overcome lung cancers were combined with YPFS in treating cultured A549/DDP cells. Amongst these herbal extracts, the extract of Ginkgo Folium exhibited the most promoting effect on the YPFS-induced cell death in cultured A549/DDP cells. This new herbal formula, named as YPFS_+GF, promoted the sensitized effect on DDP-induced toxicity by over 2-fold as compared to that of YPFS alone. The anti-resistant effect of YPFS_+GF was triggered by an increase of intracellular concentration of DDP. This anti-multidrug resistance effect of YPFS_+GF was revealed to be mediated by down regulation of WT1/MVP axis, as well as the downstream anti-apoptotic pathway of mTORC2/AKT signalling.

There are two major components in Ginkgo Folium, ginkgolide and flavonoids. In cancer therapy, flavonoids have been most intensively studied, e.g. quercetin, kaempferol, isorhamnetin. Previous screening revealed that a bioflavonoid, ginkgetin, exhibited lower IC₅₀ than that of DDP in NSCLC cells. This anti-cancer effect of ginkgetin was illustrated in a xenograft nude mouse model. Ginkgetin induced autophagic cell death in A549 cells, and this effect was markedly reversed by chemical and genetic approaches. Ginkgetin showed potential binding affinity to p62. Upregulation of p62 through chemical and genetic means decreased cell death, lysosome acidification, and autophagosome formation, which consequently disrupted autolysosome formation. In addition, the decreased autophagy induced by p62 overexpression increased Nrf2/ARE activity and the oxygen consumption rate, as well as decreased on formation of reactive oxygen species. These phenomena were exhibited in a reciprocal manner when p62 was knocked down. Thus, p62 might be a potential target in ginkgetin-induced autophagic cell death.

In conclusion, our study first illustrated the effect of YPFS in mediating the chemosensitivity of DDP. The sensitized effect of YPFS in drug resistant cells was further promoted by the addition of Ginkgo Folium. Furthermore, an active compound from Ginkgo Folium was found to induce autophagic cell death in NSCLC. Herbal medicine is one of the main adjuvant therapies in NSCLC. The novel re-formula YPFS_+GF and ginkgetin are proposed to be developed as non-canonical ways on NSCLC treatment.