Improved synergistic anticancer efficacy of quercetin in combination with PI-103, rottlerin, and G0 6983 against MCF-7 and RAW 264.7 cells
- 50 Downloads
Flavonoids have been chronicles of the history of a long way journey in the cure of physiological or pathophysiological conditions in various diseases including cancer. Our previous findings suggest the extensive mechanism of quercetin (QUE) mediated regression of cell survival, cell proliferation, oxidative stress, inflammation, and angiogenesis via modulating PI3K and PKC signaling in lymphoma as well as hepatocellular carcinoma. PI3K-PKC pathway is a key monitor of mammalian cells regulated by its different isoenzymes, which may exert similar or opposite cellular effects by differential coupling of signaling pathways. Put forward the invention of selective inhibitors against various isoenzymes is beneficial to reduce the burden of inclusive deleterious effects of drug for normal physiological process. Therefore, we hypothesized the improved anticancer efficacy of QUE in combination with isoenzyme inhibitors—rottlerin (ROT-PKCδ inhibitor), G0 6983 (PKCα inhibitor), and PI-103 (p110α-class I PI3K inhibitor) in MCF-7 and RAW 264.7 cells. QUE significantly improves the cytotoxicity of ROT + G0 6983 ranged 30–55% and PI-103 ranged 24–63% after 24–48 h against MCF-7 cells. Additionally in the presence of QUE, the improved cytotoxicity of ROT + G0 6983 is observed to range 69–75% and PI-103 ranged 45–88% after 24–48 h in RAW 264.7 cells. This increment in cell deaths are positively correlated with enhanced morphological alteration observed in MCF-7 cells. Further, QUE significantly increases the attenuation of PKCα level approximately by 50% in combination with PI-103. Overall results of the current study suggested that QUE improves the synergistic anticancer efficacy in combination with PI-103, ROT, and G0 6983 in MCF-7 and RAW 264.7 cells.
KeywordsQuercetin PI-103 Rottlerin G0 6983 PI3K PKC MCF-7 RAW 264.7
MV is thankful to UGC-CAS program to Department of Zoology for infrastructural facilities.
This research was supported by University Grants Commission (UGC), India (Project No. F 40-209/2011 (SR) dated June 29, 2011) and CSIR, India, for JRF & SRF (CSIR Award No. File No. 09/013(0338)/2010-EMR-I).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schäfer B, Hirsch-Ernst KI, Lampen A (2017) Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res 62. https://doi.org/10.1002/mnfr.201700447
- Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, Kearsley JH, Li Y (2014) PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways. Cell Death Dis 5:e1437CrossRefGoogle Scholar
- Djuzenova CS, Fiedler V, Katzer A, Michel K, Deckert S, Zimmermann H, Sukhorukov VL, Flentje M (2016) Dual PI3K and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiation schedule. Oncotarget 7(25):38191–38209CrossRefGoogle Scholar
- Hayakawa M, Kaizawa H, Moritomo H, Koizumi T, Ohishi T, Okada M, Ohta M, Tsukamoto S, Parker P, Workman P, Waterfield M (2006) Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem 14:6847–6858CrossRefGoogle Scholar
- Juneja M, Kobelt D, Walther W, Voss C, Smith J, Specker E, Neuenschwander M, Gohlke BO, Dahlmann M, Radetzki S, Preissner R, von Kries JP, Schlag PM, Stein U (2017) Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1. PLoS Biol 15(6):e2000784. https://doi.org/10.1371/journal.pbio.2000784 CrossRefGoogle Scholar
- Kavithaa K, Sumathi S, Paulpandi M, Padma PR (2014) Increased anticancer efficacy by the combined administration of quercetin in multidrug resistant breast cancer cells. BMR Cancer Res 1:1–13Google Scholar
- Maurya AK, Vinayak M (2016b) Breast cancer stem cell mediated aberrant signaling and epithelial-mesenchymal transition targets: hope for breast cancer therapy. Int J Cancer Oncol 3(3):1–7Google Scholar
- Ohno I, Eibl G, Odinokova I, Edderkaoui M, Damoiseaux RD, Yazbec M, Abrol R, Goddard WA 3rd, Yokosuka O, Pandol SJ, Gukovskaya AS (2010) Rottlerin stimulates apoptosis in pancreatic cancer cells through interactions with proteins of the Bcl-2 family. Am J Physiol Gastrointest Liver Physiol 298:63–73CrossRefGoogle Scholar
- Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM, Koker M, Heynck S, Stuckrath I, Weiss J, Fischer F, Michel K, Goel A, Regales L, Politi KA, Perera S, Getlik M, Heukamp LC, Ansen S, Zander T, Beroukhim R, Kashkar H, Shokat KM, Sellers WR, Rauh D, Orr C, Hoeflich KP, Friedman L, Wong KK, Pao W, Thomas RK (2009) Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci U S A 106:18351–18356CrossRefGoogle Scholar
- Zhu Y, Wang M, Zhao X, Zhang L, Wu Y, Wang B (2017) Hu W. Rottlerin as a novel chemotherapy agent for adrenocortical carcinoma. Oncotarget 8(14):22825–22834Google Scholar