Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment

Abstract

Background:Bortezomib is a proteasome inhibitor with minimal clinical activity as a monotherapy in solid tumours, but its combination with other targeted therapies is being actively investigated as a way to increase its anticarcinogenic properties. Here, we evaluate the therapeutic potential of co-treatment with bortezomib and indole-3-carbinol (I3C), a natural compound found in cruciferous vegetables, in human ovarian cancer.Methods:We examined the effects of I3C, bortezomib and cisplatin in several human ovarian cancer cell lines. Synergy was determined using proliferation assays and isobologram analysis. Cell cycle and apoptotic effects were assessed by flow cytometry. The mechanism of I3C and bortezomib action was determined by RNA microarray studies, quantitative RT–PCR and western blotting. Antitumour activity of I3C and bortezomib was evaluated using an OVCAR5 xenograft mouse model.Results:I3C sensitised ovarian cancer cell lines to bortezomib treatment through potent synergistic mechanisms. Combination treatment with bortezomib and I3C led to profound cell cycle arrest and apoptosis as well as disruptions to multiple pathways, including those regulating endoplasmic reticulum stress, cytoskeleton, chemoresistance and carcinogen metabolism. Moreover, I3C and bortezomib co-treatment sensitised ovarian cancer cells to the standard chemotherapeutic agents, cisplatin and carboplatin. Importantly, in vivo studies demonstrated that co-treatment with I3C and bortezomib significantly inhibited tumour growth and reduced tumour weight compared with either drug alone.Conclusion:Together, these data provide a novel rationale for the clinical application of I3C and bortezomib in the treatment of ovarian cancer.

Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors

“…For instance, the toxicity of bortezomib was enhanced by ER stressors and dysregulators of the UPR such as TNF in colon cancer cells (Nowis et al., 2007), the multi‐kinase inhibitor sorafenib in hepatic cancer cells (Honma and Harada, 2013), eayarestatin—an inhibitor of the ER associated ATPase p97 that retro‐translocates proteins from the ER to the proteasome—in cervical cancer cells (Brem et al., 2013), Bcl‐2 antagonists in diffuse lymphocytic B‐cell lymphoma (Dasmahapatra et al., 2009), tunicamycin and thapsigargin in pancreatic cancer cells (Nawrocki et al., 2005), and photodynamic therapy in cervical cancer cells (Szokalska et al., 2009). In ovarian cancer cells, bortezomib increased the toxicity of TRAIL (Saulle et al., 2007), histone deacetylase inhibitors (Bazzaro et al., 2008; Fang et al., 2011), carboplatin (Al‐Eisawi et al., 2013), and the natural compound indole‐3‐carbinol (Taylor‐Harding et al., 2012). Here we show that mifepristone‐induced ER stress aggravation, combined with proteasome inhibition, provides preclinical therapeutic advantage towards ovarian cancer cells—i.e.…”

Cyclin E1 and RTK/RAS signaling drive CDK inhibitor resistance via activation of E2F and ETS

“…Western blot and protein detection was performed as previously described [43]. The following primary antibodies were used: RB, phospho-RB S807/S811 , CDC25C, phospho-AKT S473 , phospho-cyclin E1 T62 , phospho-ERK1/2 T202/Y204 , ERBB2, phospho-ERBB2 Y1221/1222 and MYC (Cell Signaling, Danvers, MA); BRCA1, p53, cyclin E, CDK1, CDK2, ETV4, ETV5 and HRAS (Santa Cruz Biotechnology, Santa Cruz, CA); Actin (Abcam, Cambridge, MA); GAPDH (Fitzgerald, Acton, MA); β-Actin (Sigma-Aldrich); PAX8 (Epitomics, Burlingame, CA);…”

“…Total RNA isolation, cDNA generation and qPCR were performed as previously described [43]. Primer sequences used for qPCR were obtained from SAB Biosciences (Valencia, CA; Supplemental Information).…”

Current principles of effective therapy for ovarian cancer

“…Тем не менее несмотря на проводимую терапию число ранних реци-дивов РЯ составляет около 30 %, поздних -60-65 %, большинство из которых проявляют лекарственную устойчивость к последующим курсам химиотерапии [11,12]. Учитывая столь скромные показатели, стано-вится очевидным стремление онкологов привнести изменения в существующую схему лечения для дости-жения более высоких результатов.…”

“…Cреди известных противоопухолевых соединений растительного происхождения с мультитаргетной ак-тивностью особого внимания заслуживают пищевые индолы: индол-3-карбинол (I3C), его физиологический метаболит 3,3 , -дииндолилметан (DIM) и флавоноид эпигаллокатехин-3-галлат (EGCG), об этом имеется огромное количество публикаций [11,12,[17][18][19][20][21].…”