Paclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of chemoresistant cells represents a major challenge in chemotherapy. Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2′-7′-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity. Additionally, we confirmed that dacomitinib inhibits chemoresistance in paclitaxel-resistant ovarian cancer HeyA8-MDR cells. Collectively, our research indicated that dacomitinib effectively resensitized paclitaxel in SKOV3-TR cells by inhibiting EGFR signaling and elevating intracellular ROS levels.

Ovarian cancer is the leading cause of death among gynecologic cancers. Paclitaxel is used as a standard first-line therapeutic agent for ovarian cancer. However, chemotherapeutic resistance and high recurrence rates are major obstacles to treating ovarian cancer. We have found that tephrosin, a natural rotenoid isoflavonoid, can resensitize paclitaxel-resistant ovarian cancer cells to paclitaxel. Cell viability, immunoblotting, and a flow cytometric analysis showed that a combination treatment made up of paclitaxel and tephrosin induced apoptotic death. Tephrosin inhibited the phosphorylation of AKT, STAT3, ERK, and p38 MAPK, all of which simultaneously play important roles in survival signaling pathways. Notably, tephrosin downregulated the phosphorylation of FGFR1 and its specific adapter protein FRS2, but it had no effect on the phosphorylation of the EGFR. Immunoblotting and a fluo-3 acetoxymethyl assay showed that tephrosin did not affect the expression or function of P-glycoprotein. Additionally, treatment with N-acetylcysteine did not restore cell cytotoxicity caused by a treatment combination made up of paclitaxel and tephrosin, showing that tephrosin did not affect the reactive oxygen species scavenging pathway. Interestingly, tephrosin reduced the expression of the anti-apoptotic factor XIAP. This study demonstrates that tephrosin is a potent antitumor agent that can be used in the treatment of paclitaxel-resistant ovarian cancer via the inhibition of the FGFR1 signaling pathway.

Excessive accumulation of reactive oxygen species from exogenous and endogenous stressors can cause cellular damage. Chlorella contains diverse bioactive compounds, and violaxanthin, a major carotenoid pigment found in Chlorella sp. HS-V, has been reported to possess anti-inflammatory, anticancer, and antioxidant properties. We investigated the effect of violaxanthin on hydrogen peroxide (H₂O₂)-induced oxidative stress in human keratinocytes. Chlorella sp. HS-V extract significantly restored the H₂O₂-induced decrease in cell viability. Similarly, violaxanthin reduced H₂O₂-induced cytotoxicity and intracellular reactive oxygen species levels, which was associated with the upregulation of antioxidant enzyme expression. Under H₂O₂-induced oxidative stress conditions, violaxanthin may enhance cellular antioxidant defense by promoting nuclear factor erythroid 2-related factor 2 (NRF2) translocation through the phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase 3β (PI3K/AKT/GSK3β) signaling pathway. Additionally, violaxanthin improved H₂O₂-impaired wound healing in HaCaT human keratinocyte cells and reduced senescence-associated beta-galactosidase-positive normal human epidermal keratinocytes. Overall, these findings suggest that violaxanthin may serve as a potential therapeutic agent for mitigating oxidative stress-induced cellular dysfunction.