bims-meluca 2021-03-21 papers

FEBS Open Bio. 2021 Mar 13.

Interleukin-36α suppresses growth of non-small cell lung cancer in vitro by reducing angiogenesis.

Xiaoxiao X, Hu H, He J, Liu Y, Guo F, Luo F, Jiang M, Wang L.

Interleukin-36α, a newly recognized IL-1 family member, has been previously reported to play a pivotal role in autoimmunity diseases and acute inflammatory reactions. Recently, several studies have indicated that IL-36α has potential anti-cancer effects against certain types of cancer. However, the expression pattern and functional role of IL-36α in non-small cell lung cancer (NSCLC) have not been elucidated. Here, we report that the mRNA and protein levels of IL-36α are significantly reduced in NSCLC tissues. Low levels of intratumoral IL-36α are correlated with higher tumor status, advanced TNM stage, increased vascular invasion, and shorter overall survival (OS). Intratumoral IL-36α expression is an independent prognostic factor for OS (hazard ratio = 3.081; P = 0.012) in NSCLC patients. Overexpression of IL-36α in lung cancer cells did not disturb cell proliferation, apoptosis, or cell cycle distribution in vitro, but markedly inhibited tumor growth in vivo. Mechanistically, IL-36α reduced the expression and secretion of vascular endothelial growth factor A (VEGFA) through inhibiting HIF-1α expression. Finally, decreased IL-36α expression was associated with high MVD and VEGFA in NSCLC patients. Together, our findings suggest that IL-36α expression is a valuable marker indicating poor prognosis in NSCLC patients.

Keywords: Angiogenesis; Interleukin-36α; Non-small cell lung cancer; VEGFA

DOI: https://doi.org/10.1002/2211-5463.13141

Int Immunopharmacol. 2021 Mar 11. pii: S1567-5769(20)33825-X. [Epub ahead of print] 107357

Isovitexin potentiated the antitumor activity of cisplatin by inhibiting the glucose metabolism of lung cancer cells and reduced cisplatin-induced immunotoxicity in mice.

Chen RL, Wang Z, Huang P, Sun CH, Yu WY, Zhang HH, Yu CH, He JQ.

The increased resistance and toxicity have become the main causes of chemotherapy failure for treating lung cancer. The combination of chemotherapeutic drugs with other agents has been recognized as a promising strategy to overcome these difficulties. Isovitexin (IVT) is a well-known flavone C-glycoside found in many plants and has attracted wide attention due to its obvious antitumor and antioxidant effects. In this study, we investigated the synergistic effects of IVX and cisplatin (DDP) in non-small cell lung cancer (NSCLC) A549 and H1975 cells. The results showed that the combined treatment with IVT and DDP markedly inhibited proliferation and induced apoptosis of the two NSCLC cells. Using a mouse model of A549 xenograft, IVT potentiated the inhibition of DDP on tumor growth, but reduced DDP-induced hepatotoxicity and nephrotoxicity in mice. Remarkedly, IVT promoted lipopolysaccharide (LPS)- and lectin- stimulated splenocyte proliferation, and enhance cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activities as well as the production of IL-2 and TNF-α. Furthermore, IVT significantly reduced glucose uptake, lactate production, and ATP production, and downregulated the protein expressions of pyruvate kinase M2 (PKM2)-mediated pathway in both A549 and H1975 cells. After the over-expression of PKM2 in the NSCLC cells, the synergistic antitumor effect of IVT and DDP was markedly weakened. Therefore, IVT not only inhibited cell proliferation and glucose metabolism via downregulating the expression of PKM2 to enhance the antitumor activity of DDP against lung cancer cells, and improved DDP-induced immunotoxicity in mice. It also presented a novel strategy to enhance the anti-tumor effect of platinum-based chemotherapy against NSCLC.

Keywords: Apoptosis; Flavone; Glucose metabolism; PKM2; Synergistic effect

DOI: https://doi.org/10.1016/j.intimp.2020.107357

Naunyn Schmiedebergs Arch Pharmacol. 2021 Mar 18.

Sensitization of A-549 lung cancer cells to Cisplatin by Quinacrine-loaded lipidic nanoparticles via suppressing Nrf2 mediated defense mechanism.

Ahmadian S, Sabzichi M, Rashidi M, Mohammadian J, Mahmoudi S, Maroufi NF, Ramezani F, Ghorbani M, Mohammadi M, Pirouzpanah M, Bijanpour H.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is believed to be responsible for the control mechanisms of cellular defense response and master regulator of antioxidant system by adjustment of endogenous antioxidants, phase II detoxifying enzymes and transporters, so inhibition of Nrf2 could be considered molecule target to overcome drug resistance and cancer progression. By harnessing liposome as an advanced nanoparticles transporter, we formulated Quinacrine known as nrf2 inhibitor into nano-carrier, and sensitized A-549 lung tumor cells to Cisplatin. The aim of this work was to prepare liposome nano-carriers to enhance the bioavailability of Quinacrine and to improve passive targeting in A549 cells. Quinacrine formulation into liposome exposed a mean particle size of 80±5 nm in passive targeting and 110±3 after decoration with chitosan oligosaccharides (COS), respectively. The highest amount of cell death (p<0.05) occurred with the co-incubation of the A549 cells with new formulation and Cisplatin. Additionally, Quinacrine-loaded liposomes declined Nrf2 expression more than Quinacrine alone (p<0.05). Correspondingly, the expression of Nrf2 downstream genes, MRP1, Trx, and bcl2 decreased significantly. Taking all the data into consideration, liposomes containing Quinacrine could ameliorate the effectiveness of Cisplatin by raising the permeability of cancer cells to the abovementioned chemical treatment and might be then given as a candidate to boost the therapeutic protocols in cancer patients.

Keywords: A549 cells; Cisplatin; Drug delivery; Nrf2; Quinacrine-loaded liposomes

DOI: https://doi.org/10.1007/s00210-021-02079-1

Transl Lung Cancer Res. 2021 Feb;10(2): 981-994

Identification of serum biomarkers to predict pemetrexed/platinum chemotherapy efficacy for advanced lung adenocarcinoma patients by data-independent acquisition (DIA) mass spectrometry analysis with parallel reaction monitoring (PRM) verification.

Jia B, Zhao X, Wu D, Dong Z, Chi Y, Zhao J, Wu M, An T, Wang Y, Zhuo M, Li J, Chen X, Tian G, Long J, Yang X, Chen H, Wang J, Zhai X, Li S, Li J, Ma M, He Y, Kong L, Brcic L, Fang J, Wang Z.

Background: Pemetrexed/platinum chemotherapy has been the standard chemotherapy regimen for lung adenocarcinoma patients, but the efficacy varies considerably.Methods: To discover new serum biomarkers to predict the efficacy of pemetrexed/platinum chemotherapy, we analyzed 20 serum samples from advanced lung adenocarcinoma patients who received pemetrexed/platinum chemotherapy with the data-independent acquisition (DIA) quantitative mass spectrometry (MS).
Results: The 20 patients were categorized as "good response" [12 patients achieving partial response (PR)] and "poor response" [8 patients with progressive disease (PD)] groups. Altogether 23 significantly different expressed proteins were identified, which had relative ratios higher than 1.2 or lower than -0.83, with 7 proteins having an area under the curve (AUC) above 0.8. To further validate the DIA results, we used the parallel reaction monitoring (PRM) method to examine 16 candidate serum biomarkers in the study cohort of 20 patients and another cohort of 22 advanced lung adenocarcinoma patients (16 PR and 6 PD). Quantitative validation using PRM correlated well with the DIA results, and 10 promising proteins exhibited a similar up- or downregulation. It is worth noting that glutathione peroxidase 3 (GPX3) exhibits significant upregulation in the poor response group compared with the good response group, which was validated by both DIA and PRM methods.
Conclusions: Our study confirmed that combined DIA MS and PRM approaches were effective in identifying serum predictive biomarkers for advanced lung adenocarcinoma patients. Further studies are needed to explore the potential biological mechanism underlying these biomarkers.

Keywords: Lung adenocarcinoma; glutathione peroxidase 3 (GPX3); mass spectrometry (MS); pemetrexed; prognosis

DOI: https://doi.org/10.21037/tlcr-21-153