Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer.

After an initial positive response to chemotherapy, cancer patients often become resistant and experience relapse. Our previous research identified eukaryotic translation initiation factor 4E (eIF4E) as a crucial target to overcome chemoresistance. In this study, we delved further into the role and therapeutic potential of myeloid cell leukemia 1 (Mcl-1), an eIF4E-mediated target, in chemoresistance. We showed that the levels of phosphor and total eIF4E, as well as Mcl-1, were elevated in chemoresistant cervical but not colon cancer cells. Mcl-1 inhibitor S64315 decreased Mcl-1 levels in chemoresistant cancer cells, regardless of Mcl-1 upregulation, decreased viability in chemoresistant cancer cells and acted synergistically with chemotherapy drugs. The combined inhibition of Mcl-1 and B-cell lymphoma 2 (Bcl-2), employing both genetic and pharmacological approaches, led to a markedly more substantial decrease in viability compared with the inhibition of either target individually. The combination of S64315 and Bcl-2 inhibitors reduced tumor growth in chemoresistant cervical and colon cancer models without causing general toxicity in mice. This combination also prolonged overall survival compared with using S64315 or venetoclax alone. Our research highlights the therapeutic potential of inhibiting Mcl-1 and Bcl-2 simultaneously in chemoresistant cancers and provides a rationale for initiating clinical trials to investigate the combination of S64315 and venetoclax for the treatment of advanced colon and cervical cancer.

Huangkui Capsule Attenuates Lipopolysaccharide-Induced Acute Lung Injury and Macrophage Activation by Suppressing Inflammation and Oxidative Stress in Mice.

Background: Huangkui capsule (HKC) comprises the total flavonoid extract of flowers of Abelmoschus manihot (L.) Medicus. This study aimed to explore the effects of HKC on lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice and LPS-stimulated RAW 264.7 cells. Methods: Enzyme-linked immunosorbent assay, histopathology, spectrophotometry, and quantitative real-time polymerase chain reaction were used for the assessments. Statistical analysis was performed using a one-way analysis of variance. Results: LPS significantly increased lung inflammation, neutrophil infiltration, and oxidative stress and downregulated lung miR-451 expression. Treatment with HKC dramatically, reduced the total cell count in the bronchoalveolar lavage fluid (BALF), and inhibited myeloperoxidase activity in the lung tissues 24 h after LPS challenge. Histopathological analysis demonstrated that HKC attenuated LPS-induced tissue oedema and neutrophil infiltration in the lung tissues. Additionally, the concentrations of tumour necrosis factor- (TNF-) α and interleukin- (IL-) 6 in BALF and IL-6 in the plasma reduced after HKC administration. Moreover, HKC could enhance glutathione peroxidase and catalase activities and upregulate the expression of miR-451 in the lung tissues. In vitro experiments revealed that HKC inhibited the production of nitric oxide, TNF-α, and IL-6 in LPS-induced RAW 264.7 cells and mouse primary peritoneal macrophages. Additionally, HKC downregulated LPS-induced transcription of TNF-α and IL-6 in RAW 264.7 cells. Conclusions: These findings suggest that HKC has anti-inflammatory and antioxidative effects that may protect mice against LPS-induced ALI and macrophage activation.