Combination of melatonin with paclitaxel reduces the TLR4-mediated inflammatory pathway, PD-L1 levels, and survival of ovarian carcinoma cells

Ovarian cancer (OC) has a high mortality rate. Although most patients respond to the conventional chemotherapy [e.g., paclitaxel (PTX)], some also develop drug resistance to make the treatment less effective. Since melatonin exhibits antioxidant, antitumor, and immunomodulatory functions in a variety of solid tumors, in this study the effects of a combination of PTX and melatonin on SKOV-3 human ovarian carcinoma cells were investigated and the focus was given to the Toll-like receptor (TLR)-mediated inflammatory pathway and cell signaling-related molecules. Flow cytometry showed that this combination significantly boosted the apoptosis/necrosis responses of the cancer cells. Cell migration was attenuated by melatonin alone, and the combination led to a reduced number of migrating and invasive cells. Melatonin alone and its combination also reduced the levels of TLR4, MyD88, TRIF, and PD-L1, but not TLR2. In addition, the combination significantly lowered the levels of NF-kB p65, PI3K, p-AKT, p38, ERK 1/2, JNK, CREB, p70s6K, and STAT5. The results suggested that this combination was effective in reducing the viability and the invasive capacity of SKOV-3 cells while increasing their apoptosis and necrosis rates. The potential mechanism of this combination is to attenuate the downstream molecules of the TLR4-mediated inflammatory pathway and cell signaling-related proteins in the cancer cells. Thus, melatonin improved the chemosensitivity of the cancer cells to PTX, serving as an effective adjuvant therapy against OC.