Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy

Abstract

One of the recently emerging anticancer strategies is the use of natural dietary compounds, such as sulforaphane, a cancer-chemopreventive isothiocyanate found in broccoli. Based on the growing evidence, sulforaphane acts through molecular mechanisms that interfere with multiple oncogenic pathways in diverse tumor cell types. Herein, we investigated the anticancer effects of bioavailable concentrations of sulforaphane in ovarian carcinoma cell line A2780 and its two derivatives, adriamycin-resistant A2780/ADR and cisplatin-resistant A2780/CP cell lines. Since tumor microenvironment is characterized by reduced oxygenation that induces aggressive tumor phenotype (such as increased invasiveness and resistance to chemotherapy), we evaluated the effects of sulforaphane in ovarian cancer cells exposed to hypoxia (2% O2). Using the cell-based reporter assay, we identified several oncogenic pathways modulated by sulforaphane in hypoxia by activating anticancer responses (p53, ARE, IRF-1, Pax-6 and XRE) and suppressing responses supporting tumor progression (AP-1 and HIF-1). We further showed that sulforaphane decreases the level of HIF-1α protein without affecting its transcription and stability. It can also diminish transcription and protein level of the HIF-1 target, CA IX, which protects tumor cells from hypoxia-induced pH imbalance and facilitates their migration/invasion. Accordingly, sulforaphane treatment leads to diminished pH regulation and reduced migration of ovarian carcinoma cells. These effects occur in all three ovarian cell lines suggesting that sulforaphane can overcome the chemoresistance of cancer cells. This offers a path potentially exploitable in sensitizing resistant cancer cells to therapy, and opens a window for the combined treatments of sulforaphane either with conventional chemotherapy, natural compounds, or with other small molecules.

Sulforaphane induces apoptosis and inhibits invasion in U251MG glioblastoma cells

“…SFN has a safe cytotoxicity profile towards the normal cells thus it can be utilized in the development of safe cancer treatment strategies (Hussain et al 2013 ; Kallifatidis et al 2011 ). In addition, sulforaphane can overcome the chemoresistance of cancer cells (Lan et al 2015 ; Pastorek et al 2015 ).…”

The Chemoprevention of Ovarian Cancer: the Need and the Options

“…Withaferin A, a steroidal lactone, synergizes with doxorubicin against OvCa, which is brought about mainly by autophagy mediated by reactive oxygen species [ 86 ]. Withaferin-A, Amla extracts, ellagic acid, and resveratrol have been reported to prevent cisplatin resistance, while sulforaphane overcomes doxorubicin and cisplatin resistance in OvCa [ 87 – 90 ]. Curcumin, epigallocatechin 3-gallate, resveratrol, lycopene, sulforaphane, and Withaferin-A modulate pathways deregulated in cancer stem cells such as Wnt/β-catenin, Sonic hedgehog, and Notch, mainly interfering with the self-renewal of cancer stem cells [ 84 , 91 ].…”

Hypoxic conditions increases H2S-induced ER stress in A2870 cells

“…Samples: cont-control, G GYY4137(10 lM), D DMOG (100 lM), and hyp 2 % hypoxia responses (p53, ARE, IRF1, Pax6, and XRE) and suppressing responses supporting tumor progression (AP1 and HIF-1). Further we have shown that sulforaphane decreases the level of HIF-1a protein without affecting its transcription and stability [25]. In this work, we focused on the role of H 2 S in ovarian tumor cells A2780.…”