Kaempferol Induces Cell Death in A2780 Ovarian Cancer Cells and Increases Their Sensitivity to Cisplatin by Activation of Cytotoxic Endoplasmic Reticulum-Mediated Autophagy and Inhibition of Protein Kinase B

El-Kott, Attalla Farag; Shati, A. A.; Al-Kahtani, M. A.; Alharbi, S. A.

doi:10.14712/fb2020066010036

Folia Biologica > Archive > 2020, Vol. 66 > Issue 1 > Kaempferol Induces Cell Death in A2780…

Fol. Biol. 2020, 66, 36-46

https://doi.org/10.14712/fb2020066010036

Kaempferol Induces Cell Death in A2780 Ovarian Cancer Cells and Increases Their Sensitivity to Cisplatin by Activation of Cytotoxic Endoplasmic Reticulum-Mediated Autophagy and Inhibition of Protein Kinase B

Attalla Farag El-Kott^1,2, A. A. Shati¹, M. A. Al-Kahtani¹, S. A. Alharbi³

¹Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
²Zoology Department, College of Science, Damanhour University, Damanhour, Egypt
³Department of Physiology, College of Medicine, Umm Al-Qura University, Mekkah, Saudi Arabia

Received July 2019
Accepted October 2019

This study investigated whether kaempferol could inhibit ovarian cancer (OC) by activation of endoplasmic reticulum (ER) stress and autophagy, and tested its effect on the sensitivity of OC cells to cisplatin (cis-diamminedichloroplatinum, DPP). To study the effect of kaempferol on activation of ER stress and autophagy and find out whether its mechanism of action involves calcium (Ca²⁺), A2780 OC cells were cultured in DMEM/F12 for 24 h with or without kaempferol (40 μmol/l) in the presence or absence of autophagy or ER stress inhibitors or a calcium chelator. To study the effect of kaempferol on the sensitivity of OC cells to DPP and the potential involvement of modulation of protein kinase B (Akt) expression, A2780 OC were incubated with kaempferol and increasing concentrations of DPP (0–20 μmol/l) and then with kaempferol at its predetermined IC₅₀ (6.8 μmol/l). Compared to control cells, kaempferol increased cell apoptosis (158 %) and decreased viability (53.17 %) and proliferation (49.17 %) of A2780 OC cells. Concomitantly, it increased the protein levels of GRP78, PERK, ATF6, IRE-1, LC3II, beclin 1, and caspase 4, thus suggesting activation of cytotoxic autophagy. This was mediated by increasing intracellular Ca²⁺ levels. In addition, kaempferol increased the sensitivity of A2780 cells to DPP (IC₅₀ from 6.867 ± 0.99 to 3.73 ± 0.59 μmol/l) by decreasing the protein levels of p-Akt (0.31 ± 0.09 vs 0.12 ± 0.005). In conclusion, the findings of this study encourage the use of kaempferol alone or in combination with DPP to inhibit tumorigenesis of ovarian cells.

Keywords

ovarian, cancer, kaempferol, apoptosis, cisplatin.

Funding

The authors extend their appreciation to the deanship of Scientific Research at King Khalid University, Abha, KSA for funding this work through the research groups program under grant number (R.G.P.1/46/39).