The Warburg effect is a peculiar feature of cancer’s metabolism, which is an attractive therapeutic target that could aim tumor cells while sparing normal tissue. Matrine is an alkaloid extracted from the herb root of a traditional Chinese medicine, Sophora flavescens Ait. Matrine has been reported to have selective cytotoxicity toward cancer cells but with elusive mechanisms. Here, we reported that matrine was able to reverse the Warburg effect (inhibiting glucose uptake and lactate production) and suppress the growth of human colon cancer cells in vitro and in vivo. Mechanistically, we revealed that matrine significantly decreased the messenger RNA (mRNA) and protein expression of HIF-1α, a critical transcription factor in reprogramming cancer metabolism toward the Warburg effect. As a result, the expression levels of GLUT1, HK2, and LDHA, the downstream targets of HIF-1α in regulating glucose metabolism, were dramatically inhibited by matrine. Moreover, this inhibitory effect of matrine was significantly attenuated when HIF-1α was knocked down or exogenous overexpressed in colon cancer cells. Together, our results revealed that matrine inhibits colon cancer cell growth via suppression of HIF-1α expression and its downstream regulation of Warburg effect. Matrine could be further developed as an antitumor agent targeting the HIF-1α-mediated Warburg effect for colon cancer treatment.
Roughly one third of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-sensitive mutated (EGFRm) tumors experience disease progression through central nervous system (CNS) metastases during treatment. Although EGFR-TKIs have been reported to be favored in some patients with EGFRm NSCLC CNS metastases, novel EGFR-TKIs with proven efficacy in CNS pathologies are clinically needed.To investigate whether almonertinib, a novel third-generation EGFR-TKI for NSCLC, can cross the blood-brain barrier (BBB) and deliver treatment for EGFR-mutant NSCLC brain metastases and spinal cord metastases, we constructed NSCLC brain metastasis and spinal cord metastasis models in vivo to observe the anti-tumor effects of almonertinib. Using ABCB1-MDCK and BCRP-MDCK monolayer cells as the in vitro study model, the effects of transport time and drug concentration on the apparent permeability coefficient of almonertinib and its active metabolite, HAS-719, were investigated. The results of this study show that almonertinib can significantly inhibit PC9 brain and spinal cord metastases. Pharmacokinetic studies in mice revealed that almonertinib has good BBB penetration ability, whereas the metabolite HAS-719 does not easily penetrate the BBB. Early clinical evidence of almonertinib activity in patients with EGFRm-advanced NSCLC and brain metastases has also been reported. In conclusion, almonertinib easily penetrates the BBB and inhibits advanced NSCLC brain and spinal cord metastases.
Stem cell therapies have attracted a lot of attention in the fields of dermatological and esthetic medicine. The paracrine action of stem cells is deemed to play a crucial role in skin treatments. Many reports have demonstrated the beneficial effects of conditioned medium (CM) derived from ADSCs on skin photoaging. However, few reports have presented the application of exosome (Exo) derived from ADSCs in the treatment of photoaging. To clarify the effects of Exo, we collected Exo from the CM of ADSCs and the photoprotective effects of Exo, as well as those of the CM with and without Exo, were investigated by detecting the intracellular ROS, DNA damage and some photoaging‐associated signal pathways on UVB‐treated human dermal fibroblasts. The results showed that Exo had significant efficiency in preventing photoaging, and it could inhibit UVB‐induced cellular DNA damage, overexpression of ROS and MMP‐1 via regulating Nrf2 and MAPK/AP‐1 pathway. In addition, Exo could effectively activate the TGF‐β/Smad pathway to elevate the expression of procollagen type I. However, these photoprotective effects were weakened when Exo was removed from the CM. Taken together, the results suggested that Exo, a key component of paracrine activity, played an important role in the treatment of photoaging.
Almonertinib, a new third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective to EGFR T790M-mutant non-small cell lung cancer (NSCLC). However, there is no available information on the form and molecular mechanism of Almonertinib-induced death in NSCLC cells. Herein, CCK-8 and colony formation assays, flow cytometry, electron microscopy, and western blots assay showed that Almonertinib inhibited NSCLC cells growth and proliferation by inducing apoptosis and autophagy which can be inhibited by a broad spectrum of caspase inhibitor Z-VAD-fmk or autophagy inhibitor chloroquine. Importantly, Almonertinib-induced autophagy was cytoprotective in NSCLC cells, and the blockade of autophagy improved cell apoptosis. In addition, Almonertinib increased reactive oxygen species (ROS) generation and clearance of ROS through pretreatment with N-acetyl-L-cysteine (NAC) inhibited the decrease of cell viability, apoptosis and increase of LC3-II induced by Almonertinib. The results of Western blot showed that both EGFR activity and downstream signaling pathways were inhibited by Almonertinib. Taken together, these findings indicated that Almonertinib induced apoptosis and autophagy by promoting ROS production in NSCLC cells.
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