Abstract
Immunotherapies have emerged as promising complementary treatments for ovarian cancer (OC), but its effective and direct role on OC cells is unclear. This study examined the combinatory effects of the protein aggregate magnesium–ammonium phospholinoleate–palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) on cell migration/invasion, apoptosis, toll-like receptor (TLR)-mediated inflammation, and cytokine/chemokine profile in human OC cell line SKOV-3. P-MAPA and IL-12 showed cancer cell toxicity under low doses after 48 h. Although apoptosis/necrosis and the cell cycle were unchanged by the treatments, P-MAPA enhanced the sensitivity to paclitaxel (PTX) and P-MAPA associated with IL-12 significantly reduced the migratory potential and invasion capacity of SKOV-3 cells. P-MAPA therapy reduced TLR2 immunostaining and the myeloid differentiation factor 88 (MyD88), but not the TLR4 levels. Moreover, the combination of P-MAPA with IL-12 attenuated the levels of MyD88, interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kB p65). The IL-12 levels were increased and P-MAPA stimulated the secretion of cytokines IL-3, IL-9, IL-10, and chemokines MDC/CCL22 and, regulated on activation, normal T cells expressed and secreted (RANTES)/CCL5. Conversely, combination therapy reduced the levels of IL-3, IL-9, IL-10, MDC/CCL22, and RANTES/CCL5. Collectively, P-MAPA and IL-12 reduce cell dynamics and effectively target the TLR-related downstream molecules, eliciting a protective effect against chemoresistance. P-MAPA also stimulates the secretion of anti-inflammatory molecules, possibly having an immune response in the OC microenvironment.
Highlights
Ovarian cancer (OC) is the fifth largest cause of cancer-related death in the United States and is the most lethal of all gynecological malignancies [1]
Because palmitoleate magnesium–ammonium phospholinoleate–palmitoleate anhydrideanhydride (P-MAPA) is thought to increase IFN-γ levels, which may potentiate the Thelper (Th1)-mediated immune response, and adjuvant therapies with IL-12 have long been proposed as beneficial for patients with ovarian cancer (OC), this study investigates the effects of P-MAPA and IL-12, alone or in combination, on cancer cell activities with focus to the toll-like receptor (TLR)-mediated inflammatory process and cytokines/chemokines profiling in human SKOV-3 cell line
Annexin V- fluorescein isothiocyanate (FITC)/Propidium iodide (PI) staining was used to effectively determine the apoptosis/necrosis rate induced by P-MAPA and rhIL-12 immunotherapies
Summary
Ovarian cancer (OC) is the fifth largest cause of cancer-related death in the United States and is the most lethal of all gynecological malignancies [1]. Immunotherapies have demonstrated great efficiency by activating host immune responses into the OC microenvironment [8]; what is happening with the cancer cells as a direct result of immunostimulation requires further investigation. We recently reported the effect of the immunomodulatory agent termed protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA), a natural biopolymer extracted from the Aspergillus oryzae, which exhibits a number of antitumor responses in different experimental models of cancer [9,10,11]. P-MAPA did not show toxicity in preclinical in vitro (V-79 Chinese hamster cell line) and in vivo models (Swiss mice, Wistar rats, and monkeys) nor in human clinical trial phase I [9]; its effects in cancer treatment have been tested in non-muscle invasive urinary bladder cancer [9,10] and in OC [11].
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