Fighting breast cancer with natural compounds backed by science

Approximately 1 in 8 women will be diagnosed with breast cancer (BrCa) sometime during their lives. Surgery, chemotherapy, radiotherapy and hormone therapy are the classical methods used to treat BrCa. But the development of drug resistance, the occurrence of side effects and reoccurrence of the disease indicate that these drugs have limited efficacy.

Right now there is an urgent need for replacing present chemotherapy drugs with natural compounds, since natural compounds affect several targets, have minimal or no side effects and are safer, cheaper and less toxic when treating BrCa.

These natural compounds are (Source Review 2020: "Role of natural compounds in preventing and treating breast cancer" by Brianna Noel, Santosh Kumar Singh, James W. Lillard, Jr., and Rajesh Singh):

Quercetin

Quercetin (QC), is a flavonol produced by plants such as Allagopappus viscosissimus and Rhamnus species, and is present in various vegetables and fruits (onions, green tea, apples, berries), in red wine, tea and coffee. Blueberries for example supply 7.67mg of QC in a 100g serving.

QC has anti-cancer, anti-oxidant, anti-tumour and anti-inflammatory properties.

In particular, QC promotes apoptosis in a wide variety of cells, including those of prostate, lung, breast, colon and cervical cancers. To promote apoptosis of cancer cells, QC decreases the expression of anti-apoptotic proteins (such as survivin, Bcl-xL and Bcl-2) and increases the expression of the pro-apoptotic proteins (such as Bad and Bax).

In addition, QC arrests proliferation of BrCa cells by inhibiting the cell cycle. Moreover, it inhibits the growth and invasive capacity of BrCa stem cells and downregulates various proteins that are associated with the growth of BrCa cells.

Tetrandrine

Tetrandrine, is an alkaloid present in Stephania tetrandra an Asian herb used for medicinal purposes, and has anti-tumour properties

Tetrandrine has pro-apoptotic effects on cancers, including leukemias, melanomas and prostate and breast cancers and has pharmacological properties that contribute to the blockade of various drug resistance proteins.

For example, tetrandrine can reverse drug resistance of tamoxifen (a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men).

Further, tetrandrine induces autophagy. As a result, cells that are resistant to apoptosis (low expression of caspase 3, caspase 7, Bax, Bak) undergo autophagic cell death when treated with tetrandrine.

Tetrandrine has also a preventive effect against the growth of inflammatory and breast tumour-initiating cells by killing these cells. In addition tetrandrine has also anti-proliferative properties by reducing mammosphere formation, which is a surrogate for the proliferation of breast cancer cells.

Treatment with tetrandrine and arsenic (used in chemotherapy, such as arsenic trioxide, stops the growth of tumour cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading) induces cycle phase arrest and promotes autophagy.

Curcumin

Curcumin (CUR), a component of the spice plant Curcuma longa or turmeric, has anti-inflammatory, anti-microbial, anti-oxidative and anticancer properties on squamous cell carcinomas and on lung, breast, pancreatic, brain, head and neck and colorectal cancers.

So far, we know that CUR in BrCa

• promotes apoptosis;
• blocks angiogenesis ("Fighting angiogenesis with natural compounds backed by science" Via Vocal) and tumour metastasis;
• prevents the activation of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells), an important signalling pathway that is involved extensively in cancer development and progression;
• CUR reduces paclitaxel-induced NF-κB;
• downregulates the expression of human epidermal growth factor 2 (HER2 has a big role in the development of certain aggressive types of breast cancer) and the phosphorylation of Akt (an attractive treatment option for breast cancer subtypes resistant to conventional treatments);
• promotes cell cycle arrest; and
• inhibits epithelial-mesenchymal transition (EMT) markers (EMT is a developmental program that enables cancer cells to suppress their epithelial features changing to mesenchymal ones and acquire mobility and the capacity to migrate from the primary site).

Finally, CUR reduces the proliferative effects of bisphenol A (an industrial chemical that has been used to make certain plastics and resins since the 1950s), which is associated with the development of BrCa.

So far, phase I clinical trials have shown safety, tolerability and nontoxicity of curcumin even at high doses (8 g/day) but exhibited poor bioavailability in humans (Source). Despite these bioavailability issues, clinical trials with curcumin have shown efficacy against breast cancer.

For example, a phase 2/3 trial to determine the efficacy of curcumin (300 mg/day) with paclitaxel (80 mg/m2) against advanced and metastatic breast cancer patients (NCT03072992), caused no major safety issues and no reduction in quality of life, it may be beneficial in reducing fatigue, and was superior to the paclitaxel-placebo combination after 12 weeks of treatment.

Combined treatment with curcumin and berberine (has the ability to overcome multidrug resistance indicating its potential in tumour chemotherapy) promotes caspase-dependent apoptosis and initiates autophagy.

Silibinin

Silibinin (INN), from the plant Silybum marianum a milk thistle, possesses hepatoprotective, anti-inflammatory, anti-fibrotic and anti-tumour effects on various cancers, including those of the breast, colon, prostate, skin, brain and lung.

So far, we know that INN in BrCa

• induces apoptosis;
• initiates autophagy;
• diminishes Reactive oxygen species (ROS) production;
• lowers EGF-induced Fibronectin (FN) expression; FN is associated with cell adhesion, migration and oncogenic transformation, and its expression correlates with a poor prognosis for various types of cancer, including BrCa. And
• downregulates the expression of Matrix metalloproteinases (MMPs) that contribute to cell migration, cell invasion and cancer metastasis.

Overall, INN has anti-proliferative and anti-migratory effects on BrCa cells, and reduces tumour sizes in mice.

Combined treatment with silibinin and chrysin (a flavonoid that inhibits proliferation and induces apoptosis in most cancer cells) suppresses BrCa cell proliferation.

Thymoquinone

Thymoquinone (TQ), is present in the seeds of Nigella sativa, and has activity against myeloblastic leukemia, osteosarcoma, pancreatic adenocarcinoma, breast, liver, ovarian, larynx, prostate and colorectal cancers.

So far, we know that TQ in BrCa

• promotes apoptosis;
• promotes cell cycle arrest;
• hinders tumour growth by targeting NF-κB; and
• it serves as a ligand of PPAR-γ (peroxisome proliferator-activated receptors) and inhibits proliferation of BrCa. PPAR-γ play an essential role in the regulation of cellular differentiation/development/metabolism and tumorigenesis.

Treatment with thymoquinone and tamoxifen (a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men) diminishes relapse rates and promotes apoptosis.

Resveratrol

Resveratrol (RES), a polyphenolic compound with anti-carcinogenic activity, is present in plant foods and dietary sources, including grapes, peanuts, soybeans, pomegranates and berries. A plant that contains considerable amounts of resveratrol is Polygonum cuspidatum or Reynoutria japonica or Japanese knotweed, which has beneficial effects against inflammation.

So far, we know that RES in BrCa

• prevents tumorigenesis, DNA damage and cancer metastasis;
• induces cell cycle arrest and apoptosis;
• hinders cyclooxygenase (COX) activity, responsible for the formation of mediators of inflammatory and anaphylactic reactions. Constitutive overexpression of COX-2 is a ubiquitous driver of mammary carcinogenesis;
• diminishes DNA binding activity of NF-κB;
• reduces cell viability, glucose consumption and ATP content; and
• induces autophagy.

Treatment with resveratrol and salinomycin (an antibacterial and coccidiostat ionophore therapeutic drug that kills breast cancer stem cells in mice at least 100 times more effectively than the anti-cancer drug paclitaxel) regulates the cell cycle, initiates apoptosis and suppresses cell migration and invasion.

Honokiol

Honokiol (HNK), is a natural compound derived from the plant Magnolia grandiflora that has anti-microbial, anti-oxidative and anti-inflammatory properties.

Regarding HNK's effectiveness in BrCa therapy, we know that

• inhibits angiogenesis;
• prevents tumour cell proliferation and induces apoptosis;
• in glioma, breast and prostate cancer cells, it diminishes immuno-resistance, an emerging problem in immunotherapy;
• inhibits phospholipase D (PLD) activity; the survival of cancer cells is greater when PLD activity is enhanced; and
• suppresses mammosphere formation.

Mammosphere formation is considered an indicator of a stem-like phenotype in tumour cells and HNK demonstrated anti-cancer effects on BrCa cells through suppression of mammosphere formation and suppression of the stem-like phenotype of BrCa cells.

Treatment with honokiol and lapatinib (tyrosine kinase inhibitor which interrupts the HER2/neu) suppresses tumour cell growth and promotes apoptosis in cells over-expressing HER-2.

Diosgenin

Diosgenin (DG) is a steroid saponin derived from the plants Dioscorea villosa (or Wild yam) and Trigonellafoenum graecum.

DG has anti-hypercholesterolemia, anti-hyperglycemia, anti-fungal, anti-viral, anti-diabetes properties, suppresses tumour growth and progression, and promotes apoptosis. The cancers beneficially affected by DG include osteosarcoma, colon carcinoma, leukemia, hepatoma and BrCa. So far, there are no reports indicating a toxic effect on non-cancerous cells.

Regarding DG's effectiveness in BrCa therapy, we know that

• suppresses cancer growth and progression;
• promotes apoptosis;
• inhibits actin polymerisation and inhibits ER-α protein;
• induces the intrinsic antioxidant defence system;
• activates GATA Binding Protein 3 (GATA3). Low GATA3 expression correlates with a poor prognosis for BrCa patients, so DG can be beneficial as it induces the expression of GATA3; and
• downregulates MMP9.

Genistein

Genistein, an isoflavone phytoestrogen present in Leguminosae (Fabaceae), and notably in soybeans. The compound overcomes cancer drug resistance and suppresses the recurrence of cancers.

Regarding genistein's effectiveness in BrCa therapy, we know that

• reduces tumorigenesis of cancers that require estrogen;
• induces cell differentiation;
• promotes cell cycle arrest;
• promotes apoptosis, suppresses angiogenesis and metastasis; and
• inactivates the epidermal growth factor (EGF) signalling pathway, that plays a central role in the pathogenesis of several human cancers.

Administered to rats, genistein prevents tumours, cardiovascular disease and osteoporosis, and it is a preventive agent for chemically induced mammary tumours.

In clinical practice, this compound has the potential to increase survival rates of patients with BrCa.

Garcinol

Garcinol, is a polyisoprenylated benzophenone extracted from the plant Garcinia (other common are Garcinia cambogia, brindle berry and Malabar tamarind), and possesses anti-oxidative, anti-bacterial, anti-fungal, anti-inflammatory, anti-glycative and anticancer characteristics.

Regarding garcinol's effectiveness in BrCa therapy, we know that

• down-regulates the NF-κB signalling pathway;
• suppresses ROS;
• induces cell cycle arrest; and
• reverses EMT markers and prevents cancer migration.

Finally, combined treatment with garcinol and paclitaxel promotes cell cycle arrest, blocks the NF-κB signalling pathway, inhibits cell viability, inflammation, angiogenesis and cell migration.

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