Using Liposomes to Alleviate the Toxicity of Chelerythrine, a Natural PKC Inhibitor, in Treating Non-Small Cell Lung Cancer

Abstract

Aim of the StudyCHE can inhibit the proliferation of lung cancer cells and induce apoptosis. However, despite having in vivo toxicity, CHE has not been thoroughly investigated in term of its in vivo antitumor effect. The present study evaluated the antitumor effect of CHE on non-small cell lung cancer cell line HCC827.MethodsThe antitumor effect of CHE on HCC827 was evaluated, and its potential work mechanism was investigated. CHE long circulation liposomes (CHELPs) modified with polyethylene glycol have been optimized and characterized by in vivo pharmacokinetic studies. A HCC827 xenograft model was developed on BALB/c nude mice for the assessment of the effects of CHE and CHELP.ResultsCHE might inhibit HCC827 growth through the ROS/PKC-ϵ/caspase 3 pathway and glycolysis. The optimized CHELP remained stable after storage for 10 days at 4°C and exhibited sustained drug release, showing approximately one-fifteenth of the in vivo clearance rate and 86 times the absorption concentration of free drug. While increasing the bioavailability of CHE, CHELP showed a good therapeutic effect on HCC827 tumor-bearing nude mice and reduced the toxicity of the free drug, improving the safety of CHE.ConclusionsCHE is a candidate drug for NSCLC, and liposomes are effective in alleviating the toxicity of CHE.

Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids

“…Moreover, the main mechanism of action is correlated with the alteration of phosphoinositide 3-kinase (PI3K), Akt, and the mammalian target of rapamycin (mTOR) signaling pathways [ 35 ]. Chelerythrine ( 2 ) has exhibited anticancer activity in vivo and in vitro, and considerable existing research has confirmed that chelerythrine can act on different pathways (e.g., DNA, MAPK, apoptosis, ROS, cell cycle, autophagy, tumor metastasis, and PKC) to inhibit or facilitate apoptosis in a variety of cancer cells (e.g., non-small cell lung cancer [ 36 ], prostate cancer [ 37 ], lung adenocarcinoma [ 38 ], renal cancer [ 39 ], and melanoma cells [ 40 ], colorectal cancer [ 41 ]), thus suggesting that the benzophenanthridine alkaloids exhibit high anticancer activity. Previous studies have proven that chelerythrine ( 2 ) exhibits antitumor stem cell properties, which are mediated by the downregulation of β- Catenin expression, thus inhibiting non-small cell lung cancer stem cells [ 42 ].…”

Rediscovery of Traditional Plant Medicine: An Underestimated Anticancer Drug of Chelerythrine

“…Another study on the NSCLC cell line (HCC827) reported the efficacy of CHE in inducing apoptosis and inhibiting cell growth by inducing ROS release and downregulating caspase-3 and PKC-ϵ expression. CHE imparted anticancer effects on HCC827 by inhibiting PKC and caspase-3 activation, which were blocked by PMA, a PKC activator, thereby proving that CHE inhibited cancer cell viability and proliferation and induced cell apoptosis through the ROS/PKC-ϵ/caspase three pathway and glycolysis ( Wang et al, 2021 ).…”

“…In addition, an in vivo study proved that CHE exerted specific anticancer effects on concentration adjustment to inhibit the Wnt/β-catenin pathway in different lung cancers and facilitate cancer cell apoptosis, inhibiting the proliferation and diminishing the self-renewal capacity of human lung cancer stem cells (HLCSCs) by downregulating β-catenin, SOX2, and MYC ( Heng and Cheah, 2020 ; Wang et al, 2021 ). Owing to the inhibition of the tumorigenic activity of HLCSCs by CHE, which can inhibit cancer growth, the CHE concentration can be flexibly adjusted to protect against different specific targets in different cancers.…”

“…Recent studies provide some new materials that can reduce the toxicity of CHE. Pharmacokinetic studies have revealed that CHE long circulation liposomes (CHELPs) modified with polyethylene glycol remained stable and exhibited sustained drug release while increasing the bioavailability and alleviating the toxicity of CHE, which showed a good therapeutic effect against cancer ( Li et al, 2013 ; Wang et al, 2021 ). This study showed that nanostructured material may be an effective method to reduce chelerythrine toxicity and may contribute to the development of novel drugs in clinical trials.…”

“…Recent studies proved that the biomaterial might be a suitable method to enhance the bioavailability and improve the therapeutic efficacy of CHE in vivo . The relative bioavailability of CHE in liposomes (CHELPs) was significantly increased, and CHELP has a lower clearance rate and higher absorption concentration than the free drug ( Li et al, 2013b ; Wang et al, 2021 ).…”