The tumor stroma has been described as “normal wound healing gone awry”. We explored whether the restoration of a wound healing-like microenvironment may facilitate tumor healing. Firstly, we screened three natural compounds (shikonin, notoginsenoside R1 and aconitine) from wound healing agents and evaluated the efficacies of wound healing microenvironment for limiting single agent-elicited carcinogenesis and two-stage carcinogenesis. The results showed that three compounds used alone could promote wound healing but had unfavorable efficacy to exert wound healing, and that the combination of three compounds made up treatment disadvantage of a single compound in wound healing and led to optimal wound healing. Although individual treatment with these agents may prevent cancer, they were not effective for the treatment of established tumors. However, combination treatment with these three compounds almost completely prevented urethane-induced lung carcinogenesis and reduced tumor burden. Different from previous studies, we found that urethane-induced lung carcinogenesis was associated with lung injury independent of pulmonary inflammation. LPS-induced pulmonary inflammation did not increase lung carcinogenesis, whereas decreased pulmonary inflammation by macrophage depletion promoted lung carcinogenesis. In addition, urethane damaged wound healing in skin excision wound model, reversed lung carcinogenic efficacy by the combination of three compounds was consistent with skin wound healing. Further, the combination of these three agents reduced the number of lung cancer stem cells (CSCs) by inducing cell differentiation, restoration of gap junction intercellular communication (GJIC) and blockade of the epithelial-to-mesenchymal transition (EMT). Our results suggest that restoration of a wound healing microenvironment represents an effective strategy for cancer prevention.
This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). In vitro experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive oxygen species (ROS) and decreased autophagy and therefore induced apoptosis in HL-60-N2 cells with morphological changes, but had no effect on cell viability in HL-60-N1 cells. The neutrophil-regulating efficacy of berberine was confirmed in the urethane-induced lung carcinogenic model and H22 liver cancer allograft model. Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX.
Both gingerol and capsaicin are agonists of TRPV1, which can negatively control tumor progression. This study observed the long-term effects of oral administration of 6-gingerol alone or in combination with capsaicin for 20 weeks in a urethane-induced lung carcinogenic model. We showed that lung carcinoma incidence and multiplicity were 70% and 21.2 ± 3.6, respectively, in the control versus 100% and 35.6 ± 5.2 in the capsaicin group (P< 0.01) and 50% and 10.8 ± 3.1 in the 6-gingerol group (P < 0.01). The combination of 6-gingerol and capsaicin reversed the cancer-promoting effect of capsaicin (carcinoma incidence of 100% versus 20% and multiplicity of 35.6 ± 5.2 versus 4.7 ± 2.3; P < 0.001). The cancer-promoting effect of capsaicin was due to increased epidermal growth-factor receptor (EGFR) level by decreased transient receptor potential vanilloid type-1 (TRPV1) level (P < 0.01) . The capsaicin-decreased EGFR level subsequently reduced levels of nuclear factor-κB (NF-κB) and cyclin D1 that favored enhanced lung epithelial proliferation and epithelial-mesenchymal transition (EMT) during lung carcinogenesis (P < 0.01). In contrast, 6-gingerol promoted TRPV1 level and drastically decreased the levels of EGFR, NF-κB, and cyclin D1 that favored reduced lung epithelial proliferation and EMT (P < 0.01). This study provides valuable information for the long-term consumption of chili-pepper-rich diets to decrease the risk of cancer development.
Starving tumor cells by restricting nutrient sources is a promising strategy for combating cancer. Because both berberine and cinnamaldehyde can activate AMP-activated protein kinase (AMPK, a sensor of cellular energy status), we investigated whether the combination of berberine and cinnamaldehyde could synergistically prevent lung carcinogenesis through tumor cell starvation. Urethane treatment induced lung carcinogenesis in mice, downregulated AMPK and mammalian target of rapamycin (mTOR) while upregulating aquaporin-1 (AQP-1) and nuclear factor kappa B (NF-κB). Together, berberine and cinnamaldehyde reduced mouse susceptibility to urethane-induced lung carcinogenesis, and reversed the urethane-induced AMPK, mTOR, AQP-1, and NF-κB expression patterns. In vitro, berberine and cinnamaldehyde together induced A549 cell apoptosis, prevented cell proliferation, autophagy, and wound healing, upregulated AMPK, and downregulated AQP-1. The effects of the combined treatment were reduced by rapamycin (a mTOR inhibitor) or HgCL2 (an AQP inhibitor), but not Z-VAD-FMK (a caspase inhibitor). The berberine/cinnamaldehyde combination also prevented A549 cell substance permeability and decreased intracellular ATP concentrations. These results suggest the combination of berberine and cinnamaldehyde limited both primary and adaptive nutrient acquisition by lung tumors via AMPK-reduced AQP-1 expression, which ultimately starved the tumor cells.
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