Quercetin and Apoptosis within Cancer cellsLauren WalkerAndrews University Dietetic InternApril 2015

Objectives:

•Define cellular apoptosis

•Define quercetin

•List quercetin rich food sources

•Explain how quercetin initiates apoptosis

Apoptosis

•Pre-programmed cell death▫Cell shrinkage▫Nuclear condensation▫Nuclear fragmentation▫Loss of adhesion to extracellular matrix

What is quercetin?

Quercetin

Flavonoid

Anti-inflammatory

Anti-viral

Anti-tumor

Hypothesis:

•Can dietary quercetin initiate apoptosis within cancer cells?

?

Additional Questions:

•Dose of quercetin?

•Side effects of increased quercetin?

Forms of Quercetin:

• Quercetin tablets

•Quercetin powder

•Emergen-C

•Quercetin found in food

Quercetin-containing FoodsOnion 41.9 mg

Asparagus 23.6 mg

Romaine lettuce 12.0 mg

Green pepper 9.9 mg

Cherry tomato 3.3 mg

Fuji Apple 2.3 mg

Broccoli 1.6 mg

Green Tea (100 mL) 2.1 mg

100 milligrams = 330 micromoles

Comparing quercetin content (mg)

1000

mg

Supp

lem

ent

500

mg

Supp

lem

ent

Powde

red

Que

rcet

in

Emer

gen-

C

Oni

ons

Aspar

agus

Romai

ne L

ettu

ce0

200

400

600

800

1000

Zhaohui Study (2013)

•What?The effect of quercetin among cell proliferation

•Hypothesis quercetin would be able to induce apoptosis of human colon carcinoma cells (HT-29 cells) through:▫ capsases, ▫Bcl-2 family members, ▫and mitochondrial potential in HT-29 cells.

Zhaohui Study (2013)

•HT-29 Human colonic epithelial cells

• Incubated with 0, 60, 90, 120 micromoles of quercetin for 24 hours.

•Quercetin at 120 micromoles most effective (p<0.01)

•ResultsQuercetin induces the activation of capsase 9 and capsase 3, which then stimulates the apoptosis signals.

Dose-dependent apoptosis

Zhaohui L, Quanxin G. Induction of apoptosis in HT-29 cells by quercetin through mitochondrial-mediated apoptotic pathway. Animal Cells and Systems. 2013. (17) No.3 147-153

Senping et al. Study (2010)

•Focuses on Mcl-1 and Bax•Human leukemia cells (U937 and HL-60)•In Vivo

▫Reduced tumor size in quercetin exposed mice

•In Vitro

Senping et al Study (2010)

In Vitro Results:Downregulation of Mcl-1

Activation of Bax

Dose dependent

Senping C, Ning G, Zhuo Z, et al. Quercetin Induces Tumor-Selective Apoptosis through Downregulation of Mcl-1 and Activation of Bax. Clinical Cancer Research. 2010;16:5679-5691

Senping et al Study (2010)Time dependent

Senping C, Ning G, Zhuo Z, et al. Quercetin Induces Tumor-Selective Apoptosis through Downregulation of Mcl-1 and Activation of Bax. Clinical Cancer Research. 2010;16:5679-5691

Hyeonji et al study. (2013)

•Human Glioblastoma Cells (U373MG cells)

Mitochondri

al Apoptosis

Protective

Autophagy

Hyeonji et al study. (2013)

Hyeonji K et al. Quercetin Induces Mitochondrial Mediated Apoptosis and Protective Autophagy in Human Glioblastoma U373MG Cells. Oxidative Medicine and Cellular Longevity. 2013. Article ID 596496. 10 pages

Hyeonji et al study (2013)Sub G-1 phase cells

Treatment Sub G-1 Phase

Control 2.21 + 1.1

Quercetin Alone 1.45 + 0.21

Chloroquine Alone 5.18 + 0.96

Chloroquine + Quercetin

18.68 + 3.02

Hyeonji K et al. Quercetin Induces Mitochondrial Mediated Apoptosis and Protective Autophagy in Human Glioblastoma U373MG Cells. Oxidative Medicine and Cellular Longevity. 2013. Article ID 596496. 10 pages

Hyeonji et al study. (2013)

Pre-treatment of cells with chloroquine

Hyeonji K et al. Quercetin Induces Mitochondrial Mediated Apoptosis and Protective Autophagy in Human Glioblastoma U373MG Cells. Oxidative Medicine and Cellular Longevity. 2013. Article ID 596496. 10 pages

Hyeonji Kim et al study. (2013)

•Quercetin combined with an autophagy inhibitor may be an excellent therapeutic approach. ▫First de-sensitize▫Then attack!

Summary• Quercetin has been shown to induce apoptosis

within different types of cancer cells.▫Capsase-9, Capsase-3 ▫Bcl-2 family members (Mcl-1, Bax, Bcl-2)▫mitochondrial potential in HT-29 cells.

• Difficult to control the exact plasma concentration of quercetin, unsure how to dose it for individuals.

• Further research is needed on dose and different lines of cancer cells.

Questions?

Bibliography• Zhaohui L, Quanxin G. Induction of apoptosis in HT-29 cells by quercetin through

mitochondrial-mediated apoptotic pathway. Animal Cells and Systems. 2013. (17) No.3 147-153• Wong R. Apoptosis in cancer: from pathogenesis to treatment. Journal of Experimental and

Clinical cancer research. 2011, 30:87• Zhaohui L, Quanxin G. Induction of apoptosis in HT-29 cells by quercetin through mitochondrial-

mediated apoptotic pathway. Animal Cells and Systems. 2013. (17) No.3 147-153• Haruno et al. Estimated Daily Intake and Seasonal Food Sources of Quercetin in Japan.

Nutrients. 2015. 7, 2345-2358.• Walle T, Walle UK, Halushka PV. Carbon Dioxide is the major metabolite of quercetin in

humans. Journal of Nutrition. 2001. (10):2648-52• Senping C, Ning G, Zhuo Z, et al. Quercetin Induces Tumor-Selective Apoptosis through

Downregulation of Mcl-1 and Activation of Bax. Clinical Cancer Research. 2010;16:5679-5691• Hyeonji K et al. Quercetin Induces Mitochondrial Mediated Apoptosis and Protective Autophagy

in Human Glioblastoma U373MG Cells. Oxidative Medicine and Cellular Longevity. 2013. Article ID 596496. 10 pages

• Ouyang L et al. Programmed cell death pathways in cancer: a review of apoptosis, autophagy, and programmed necrosis. Cell Proliferation. 2012 (45) 487-498

• Guomin Niu et al. Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells. Biochemistry and Cell Biology. 2011. (43) 30-37