Dihydroartemisinin Increases the Sensitivity of Photodynamic Therapy Via NF-κB/HIF-1α/VEGF Pathway in Esophageal Cancer Cell in vitro and in vivo

Abstract

Background/Aims: Although photodynamic therapy (PDT) can relieve esophageal obstruction and prolong survival time of patients with esophageal cancer, it can induce nuclear factor-kappa B (NF-κB) activation in many cancers, which plays a negative role in PDT. Dihydroartemisinin (DHA), the most potent artemisinin derivative, can enhance the effect of PDT on esophageal cancer cells. However, the mechanism is still unclear. Methods: We generated stable cell lines expressing the super-repressor form of the NF-κB inhibitor IκBα and cell lines with lentivirus vector-mediated silencing of the HIF-1α gene. Esophageal xenograft tumors were created by subcutaneous injection of Eca109 cells into BALB/c nude mice. Four treatment groups were analyzed: a control group, photosensitizer alone group, light alone group, and PDT group. NF-κB expression was detected by an electrophoretic mobility shift assay, hypoxia-inducible factor α (HIF-1α) and vascular endothelial growth factor (VEGF) by real-time PCR, NF-κB, HIF-1α, and VEGF protein by western blot, and Ki-67, HIF-1α, VEGF, and NF-κB protein by immunohistochemistry. Results: PDT increased NF-κB activity and the gene expression of HIF-1α and VEGF in vitro and in vivo. In contrast, the DHA groups, particularly the combined DHA and PDT treatment group, abolished the effect. The combined treatment significantly inhibited tumor growth in vitro and in vivo. NF-κB activity and HIF-1α expression were also reduced in the stable IκBα expression group, whereas the former showed no change in HIF-1α-silenced cells. Conclusion: DHA might increase the sensitivity of esophageal cancer cells to PDT by inhibiting the NF-κB/HIF-1α/VEGF pathway.

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…DHA also reinforces the anti-cancer activity of chemotherapeutic agent, cisplatin, in cisplatin-resistant ovarian cancer cells [215]. Studies also demonstrate the enhancement of sensitivity by DHA in photodynamic therapy in esophageal cancer [182,216]. Therefore, this suggests that ARTs could be potential anti-cancer agents.…”

“…Since the 2015 Nobel Prize in Physiology or Medicine conferred to Chinese scientist, Youyou Tu, artemisinin drew attention to worldwide [176]. Beside from their well-established anti-malarial effects, artemisinin and its derivatives (ARTs), including dihydroartemisinin (DHA), artesunate, artemether and arteether, are also found to exhibit potent anti-cancer activities in many studies [177][178][179][180][181][182]. DHA and artesunate are the most studied ART derivatives for cancer treatment, and artesunate will be discussed in a separate section.…”

MUC3A Promotes Non-Small Cell Lung Cancer Progress via Activating NFκB Pathway and Attenuates Radiosensitivity

“…In this study, we assume VEGF was regulated in two ways. It has been reported that NFκB signaling induces angiogenesis by increasing the production of VEGF [44][45][46], angiogenesis induced by MUC3A is also mediated by NFκB activation in NSCLC. Radiation-mediate hypoxia triggers HIF-1α transcription and up-regulates VEGF expression [46,47], MUC3A knockdown may enhance radiosensitivity by promoting oxygen stress and impair HIF-1α and VEGF expression level.…”

“…It has been reported that NFκB signaling induces angiogenesis by increasing the production of VEGF [44][45][46], angiogenesis induced by MUC3A is also mediated by NFκB activation in NSCLC. Radiation-mediate hypoxia triggers HIF-1α transcription and up-regulates VEGF expression [46,47], MUC3A knockdown may enhance radiosensitivity by promoting oxygen stress and impair HIF-1α and VEGF expression level. Furthermore, MMP-2 and MMP-9 are also known to stimulate tumor angiogenesis and the epithelial-to-mesenchymal transition (EMT) through partial proteolysis of the ECM [48][49][50][51][52].…”

Dihydroartemisinin Sensitizes Mutant p53 (R248Q)-Expressing Hepatocellular Carcinoma Cells to Doxorubicin by Inhibiting P-gp Expression

“…Meanwhile, DHA induces apoptosis in human HCC cells harboring p53-null, wild-type (WT) p53, and mutant p53, respectively [23]. Furthermore, the combination of DHA and other chemotherapeutic agents plays a synergistic role in the treatment of many kinds of cancers [24,25]. However, whether DHA could enhance the sensitivity of p53 (R248Q)-expressing HCC cells to ADM and the underlying mechanism remains unknown.…”