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Open AccessArticle

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

1
Department of Obstetrics & Gynecology, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
2
Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
3
John P. Murtha Cancer Center, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA
4
Gynecologic Cancer Center of Excellence, Women’s Health Integrated Research Center at Inova Health System, 3289 Woodburn Road, Suite 370, Annandale, VA 22003, USA
5
Inova Fairfax Hospital, Department of Obstetrics & Gynecology, 3300 Gallows Road, Falls Church, VA 22042, USA
6
Department of Molecular and Cell Biology, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
*
Author to whom correspondence should be addressed.
Biomedicines 2020, 8(4), 73; https://doi.org/10.3390/biomedicines8040073
Received: 15 March 2020 / Revised: 27 March 2020 / Accepted: 30 March 2020 / Published: 31 March 2020
(This article belongs to the Section Cancer Therapeutics)
Initially, patients that respond to cisplatin (DDP) treatment later relapse and develop chemoresistance. Agents that enhance DDP effectiveness will have a significant impact on cancer treatment. We have shown pronounced inhibitory effects of the progesterone-calcitriol combination on endometrial and ovarian cancer cell growth. Here, we examined whether and how progesterone-calcitriol combination potentiates DDP anti-tumor effects in cancer cells. Ovarian and endometrial cancer cells treated with various concentrations of DDP showed a concentration-dependent decrease in cell proliferation. Concurrent treatment of cells with DDP and progesterone-calcitriol ombination potentiated anticancer effects of DDP compared to DDP-calcitriol, or DDP-progesterone treated groups. The anticancer effects were mediated by increased caspase-3, BAX, and decreased BCL2 and PARP-1 expression in DDP and progesterone-calcitriol combination-treated cells. Stimulation of the PI3K/AKT and MAPK/ERK pathways seen in cancer cells was reduced in DDP-progesterone-calcitriol treated cells. Pretreatment of cells with specific inhibitors further diminished AKT and ERK expression. Furthermore, progesterone-calcitriol potentiated the anti-growth effects of DDP on cancer cells by attenuating the expression of SMAD2/3, multidrug resistance protein- 1 (MDR-1), and ABC transporters (ABCG1, and ABCG2), thereby impeding the efflux of chemo drugs from cancer cells. These results suggest a potential clinical benefit of progesterone-calcitriol combination therapy when used in combination with DDP. View Full-Text
Keywords: cisplatin; SMAD2/3; ABC transporters; gynecological cancer; multidrug resistance protein-1 cisplatin; SMAD2/3; ABC transporters; gynecological cancer; multidrug resistance protein-1
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Paucarmayta, A.; Taitz, H.; McGlorthan, L.; Casablanca, Y.; Maxwell, G.L.; Darcy, K.M.; Syed, V. Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro. Biomedicines 2020, 8, 73.

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