Piperine Reduces Neoplastic Progression in Cervical Cancer Cells by Downregulating the Cyclooxygenase 2 Pathway

Abstract

Cervical cancer is the fourth-most common type of cancer in the world that causes death in women. It is mainly caused by persistent infection by human papillomavirus (HPV) that triggers a chronic inflammatory process. Therefore, the use of anti-inflammatory drugs is a potential treatment option. The effects of piperine, an amino alkaloid derived from Piper nigrum, are poorly understood in cervical cancer inflammation, making it a target of research. This work aimed to investigate the antitumor effect of piperine on cervical cancer and to determine whether this effect is modulated by the cyclooxygenase 2 (PTGS2) pathway using in vitro model of cervical cancer (HeLa, SiHa, CaSki), and non-tumoral (HaCaT) cell lines. The results showed that piperine reduces in vitro parameters associated with neoplastic evolution such as proliferation, viability and migration by cell cycle arrest in the G1/G0 and G2/M phases, with subsequent induction of apoptosis. This action was modulated by downregulation of cyclooxygenase 2 (PTGS2) pathway, which in turn regulates the secretion of cytokines and the expression of mitogen-activated protein kinases (MAPKs), metalloproteinases (MMPs), and their antagonists (TIMPs). These findings indicate the phytotherapeutic potential of piperine as complementary treatment in cervical cancer.

Molecular Aspects of Piperine in Signaling Pathways Associated with Inflammation in Head and Neck Cancer

“…In this respect, the secretion of the cytokines studied, IL-8, IL-1β and IFN-γ, and the expression of MAPKs (ERK and p38) were reduced following treatment with piperine, thus indicating a further mediating effect of this compound on HEp-2 and SCC-25 cells. Thus, our data corroborates other results from our research group, in which a decrease in cytokine levels (IL-8, IL-1β) and ERK and p38 was also observed in HeLa, SiHa and CaSki cervical cancer cells after treatment with piperine [35]. Other studies also mention this action of piperine in decreasing ERK and p38 in breast cancer cells [39]; in addition, Western blot results confirmed that piperine decreased the expression of JNK and p38 in human ovarian cancer cells [40].…”

Molecular Aspects of Piperine in Signaling Pathways Associated with Inflammation in Head and Neck Cancer

“…In this respect, the secretion of the cytokines studied IL-8, IL-1β, IF-γ, and the expression of MAPKs (ERK and p38) were reduced following treatment with piperine, thus indicating a further mediating effect of this compound on HEp-2 and SCC-25 cells. Thus, our data corroborates other results from our research group, in which a decrease in cytokine levels (IL-8, IL-1β) and ERK and p38 was also observed in HeLa, SiHa and CaSki cervical cancer cells after treatment with piperine [26]. Other studies also mention this action of piperine in decreasing the phosphorylation of ERK and p38 in breast cancer cells [27], in addition, Western blot results confirmed that piperine decreased the phosphorylation of JNK and p38 in human ovarian cancer cells [28].…”

Extraction, Characterization, and Evaluation of the Cytotoxic Activity of Piperine in Its Isolated form and in Combination with Chemotherapeutics against Gastric Cancer

“…The results also show that P2 displays higher cytotoxic activity, with a lower IC50 value and with a statistically significant reduction in cell viability, starting from a concentration of 12.5 µg/mL ( Figure 8 B). Other studies have also demonstrated that piperine causes a concentration-dependent reduction in cell viability of rectal [ 61 ], cervical [ 62 ], and prostate cancer cells [ 63 ]. However, the IC50 of piperine in these studies lies around 30 µg/mL, showing that piperine is even more active in metastatic gastric cancer.…”

“…Among the studied effects of piperine, both in vitro and in vivo, are included the induction of apoptosis [ 72 , 73 ], the inhibition of cell proliferation [ 63 , 74 ] with cell cycle arrest [ 70 , 73 ], and the modulation of the expression of genes and proteins involved in the processes of cell migration and invasion [ 75 , 76 ]. All these effects influence the outcome of carcinogenesis of various types of tumors, such as breast [ 77 , 78 ], cervical [ 62 , 79 ], and colorectal [ 80 , 81 ].…”