Nature Reviews Cancer Molecular targets of for cancer prevention Contents  Introduction

-derived anticancer drugs

 Target discovery methods

 Protein targets of dietary phytochemicals - Interfering with the MAPK signaling pathways - Suppressing AKT signaling - Intervening with cell cycle progression - Regulation of other oncogenic pathways by phytochemicals

 Present limits and future prospects - The importance of multi-target inhibitors - Presonalized phytochemical cancer prevention Introduction Introduction  For late-stage, the efficacy of cancer therapies remains poor overall.

Cancer prevention is now entered the arena of targeted therapies.

Dietary phytochemicals have emerged as modulators of key cellular signalling pathways. Introduction  Cancer is still a leading cause of death worldwide, overcoming of cancer has started to change from one of treatment to one of prevention.

 The WHO indicates that one-third of all cancer deaths are preventable and that diets is closely linked to cancer prevention. ⇒ Dietary phytochemicals attentioned as an effective intervention in cancer prevention.

 The development of recent cancer preventive agent is based on the discovery of precise molecular targets. Introduction  Phytochemicals • Phytochemicals are chemical compounds produced by plants, generally to help them thrive or thwart competitors, predators, or pathogens.

• Some phytochemicals have been used as poisons and others as traditional medicine.

• Phytochemicals is generally used to describe plant compounds that are under research with unestablished effects on health and are not scientifically defined as essential nutrients. Introduction

• Tamoxifen and finasteride, which have specific molecular targets, have been approved by the US FDA as cancer preventive agents.

- Tamoxifen : Tamoxifen was discovered in 1967. : Tamoxifen (TMX) is a medication that is used to prevent in women and treat breast cancer in women and men. : It is a selective estrogen-receptor modulator (SERM) that works both by decreasing factors that increase the growth of breast cells and increasing factors that decrease the growth of breast cells. : Serious side effects include a small increased risk of uterine cancer, stroke, vision problems, and pulmonary embolism. : Common side effects include irregular periods, weight loss, and hot flashes. : It may cause harm to the baby if taken during pregnancy or breastfeeding.

※ Selective estrogen receptor modulators (SERMs) are a class of drugs that act on the estrogen receptor (ER). SERMs are competitive partial agonists of the ER Introduction - Finasteride : Finasteride is a medication used for the treatment of benign prostatic hyperplasia (enlarged prostate) and pattern hair loss.

Prostate enlargement Finasteride may improve the symptoms associated with BPH such as difficulty urinating, getting up during the night to urinate, hesitation at the start of urination, and decreased urinary flow. Pattern hair loss Finasteride is sometimes used to treat pattern hair loss (androgenetic alopecia) in men only. Treatment slows further hair loss and provides about 30% improvement in hair loss after six months of treatment, with effectiveness usually only persisting as long as the drug is taken. Phytochemical-derived anticancer drugs • The effort to develop anticancer drugs began in the 1950s.

• In 1955, the US National Cancer Institute (NCI) established the Cancer Chemotherapy National Service Center to screen natural and synthetic compounds that effectively induced cancer cell death.

• Most successful FDA-approved drugs to come from this initiative is , which was isolated from the bark of the Pacific Yew tree.

• Phytochemicals, such as resveratrol, (-)-epigallocatechin callate (EGCG), [6]-gingerol and myricetin, have been reported to directly modulate various molecular signal transduction pathways. ⇒ The specific molecular and cellular targets need to be identified. Phytochemical-derived anticancer drugs Phytochemical-derived anticancer drugs • Paclitaxel - Paclitaxel was first isolated in 1971 from the Pacific yew and approved for medicaluse in 1993. - Paclitaxel is in the taxane family of medications and it works by interference with the normal function of microtubules during cell division. - Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. (, breast cancer, , Kaposi sarcoma, cervical cancer, ) - Common side effects include hair loss, bone marrow suppression, numbness, allergic reactions, muscle pains, diarrhea. - Serious side effects include heart problems, increased risk of infection, lung inflammation. - Use during pregnancy may result in harm to the unborn baby. Phytochemical-derived anticancer drugs • Resveratol - Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural , and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens such as bacteria or fungi. - Sources of resveratrol in food include the skin of grapes, blueberries, raspberries, mulberries. - Benefits inculde anti-aging and anti-cancer effects, protects cardiovascular health, prevent obesity, protect the brain and cognitive/mental health, benefits those with or prediabetes. Phytochemical-derived anticancer drugs

• (-)-epigallocatechin gallate (EGCG)

- Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is the ester of epigallocatechin

and gallic acid, and is a type of catechin.

- EGCG, the most abundant catechin in tea, is a under basic research for its potential

to affect human health and disease.

- EGCG is used in many dietary supplements. Phytochemical-derived anticancer drugs • [6]-gingerol - Gingerol, properly as [6]-gingerol, is the active constituent of fresh . - [6]-Gingerol administered by intraperitoneal injection has been used to induce a hypothermic state in rats. - Gingerol seems to be effective in an animal model of rheumatoid arthritis. - Gingerol and its analogues have a favourable toxicity profile, but are cytotoxic towards a range of cancer cell lines including blood cancer and lung cancer. - Gingerol has been investigated in vitro for its effect on cancerous tumors of the bowel, breast tissue, ovaries, and pancreas, with positive results. Phytochemical-derived anticancer drugs • Myricetin - Myricetin is a member of the class of polyphenolic compounds, with antioxidant properties. - It is commonly derived from vegetables, fruits, nuts, berries, tea, and is also found in red wine. - such as myricetin are reputed to have several health benefits such as reducing the risk of cancer and high cholesterol reduction; it also has anti-inflammatory properties.

same- Myricetin is structurally similar to fisetin, luteolin, and quercetin and is reported to have many of the functions as these other members of the flavonol class of flavonoids.

Myricetin Fisetin

Luteolin Quercetin