Artemisinin selectively decreases functional levels of estrogen receptor-alpha and ablates estrogen induced proliferation in human breast cancer cells
Breast cancer continues to haunt woman as the second leading cause of death. Its terror remains inexorable even with the advances of medical knowledge. In the US alone 1 in 8 women will be diagnosed with breast cancer in their lifetime. It is estimated that 220000 women in the United States will be diagnosed with breast cancer yearly and 40000 of them will die.
Breast cancer as do other cancers arises from the complex interaction between external and internal factors. On the list of external factors are sedentary lifestyle, night shift workers, tobacco and alcohol exposure, etc. Internal factors being the genetic makeup, lifestyle, and among them the most important factors are female and older age. Breast tissue become cancer when they lose the ability to stop dividing, remain attached to adjacent cells, and died at the programmed time. Several factors have been investigated as the cause of cancer; inherited genetic mutation being the primary suspect. However, studies revealed that only 5 – 10 % of breast cancer patients can be traced to inherited genetic mutations, of which BRCA genes mutation was the best known. Familial trait is observed in several cases with risk factors ranging from 7.8 – 21.1 %, highest in those with first degree relative with Breast Cancer. Nevertheless, the greatest risk factors still remain being female and of old age.
Breast cancer prognosis depends on many factors. The therapeutic modalities however can be reduced to the central role of estrogens. By this, breast cancer falls into two categories: estrogen sensitive and non estrogen sensitive. Studies indicated that breast cancer cells express two main estrogen receptors, namely ERα and ERβ. The proportion of these receptors determines its malignancy behavior, and therefore its therapeutic modalities and prognosis subsequently. Higher ERα : ERβ ratio correlates with higher cellular proliferation, while low ERα : ERβ ratio correlates to anti – proliferative state.
Most breast cancers expressing ERα is estrogen sensitive, and treatment modalities for this type of breast cancer involves administration of anti – estrogen drugs such as Tamoxifen and Fulvestrant. These drugs act by competitively blocking the estrogen receptors, and as a result suppress the proliferative behavior of the cancer cells. On the other hand, non estrogen – sensitive breast cancers are usually treated with surgical removal of breast tissue followed by general chemotherapy. Estrogen sensitive breast cancer proves better prognosis since anti – estrogen drugs can be administered. However, the long term administration of these drugs is not without side effect. Side effects include increase risk of endometrial cancer and events of DVTs (deep vein thrombosis).
Ever since the detailed pharmacological profiling of current anti – estrogen drugs, attention is given into researching drugs with better tolerable side effects. Among the candidates, sweet wormwood extract, Artemisinins, is highly considered due to its anti – cancer property. Artemisinin, a sesquiterpene lactone, is extracted from a Chinese plant Artemisia annua, commonly known as qinghaosu or sweet wormwood. It carries with its name millennium – long history of vast medical application by the Chinese, mainly to treat fever. In the late 1990s, Novartis filed a patent to provide Artemisinins based anti – malarial drug with remarkable result. The study of its anti – malarial properties probes into another promising anti – cancer property of Sweet wormwood Artemisinins.
Artemisinins anti cancer mechanism is currently being intensively researched; several evidences have aid the formulation of a model in which Sweet Wormwood extract Artemisinins kills cancer cells by inducing irreversible damage through ROS (reactive oxygen species) targeting cancer cells with high iron content. It also induces apoptosis in cancer cells forcing the mutated cells to commit programmed suicide. The Developmental Therapeutics Program of the National Cancer Institute, USA, analyzes the effect of Artemisinins on 55 human cancer lines, and proved the anti-cancer activity against several types of cancers including leukemia, colon cancer cell lines, melanoma, breast, ovarian, prostate, central nervous system, and renal cancer cell lines. Previous studies also shed light into its anti – angiogenesis property, effecting a cellular stasis, thus preventing proliferation and metastasis of cancer cells.
In the light of breast cancer, researchers have also proven in early studies that Artemisinins demonstrate actions on breast cancer. In a study reported in 2008 by Sundar et al, treatment of MCF7 cells (estrogen responsive human breast cancer cell line that expresses both estrogen receptor-alpha (ERα) and estrogen receptor-beta (ERβ)) with Artemisinins, phytochemical from Sweet Wormwood, effectively blocked estrogen stimulated cell cycle progression. Artemisinins is proven to down regulate ERα protein and its transcription with few to no regulatory action on ERβ, reversing the high ERα : ERβ ratio to a level near physiologic level.
Earlier study by Lai and Singh in 2006, designed in rats suggests the potential Artemisinins activity in breast cancer cells. Rats exposed to potent mammary carcinogen, 7,12-dimethylbenz(a)anthracene (DMBA), are orally administered Artemisinins. The results reflect inhibition of the mammary cancers occurrence. Since these cancer cells are estrogen sensitive, the result therefore is extrapolated to a probable mechanism by which Artemisinins disrupt estrogenic promotion in the rat mammary epithelial probably by interfering through the ERα activity.
Translating the study in human cancer cells, Sundar et al revealed that Artemisinins down regulates ERα promoter thus reducing its transcription, keeping its level low. Artemisinins treatment also ablates the induction of endogenous progesterone receptors transcripts by either E2 or PPT, and inhibited the estrogenic stimulation of a luciferase reporter plasmid driven by consensus estrogen response elements (ERE). Chromatin Immunoprecipitation assays demonstrated that Artemisinins extensively down regulates the level of ERα bound to progesterone receptor promoter, whereas the level of bound ERβ remains unchanged. The results translate into low proliferation state after the treatment with Artemisinins, a state seen normally in human mammary epithelial cells.
With these results, there is a strong suggestion for Artemisinins as adjuvant therapy together with the current anti – estrogen therapy. The combination suggests positive synergism with promising significant lower side effects of anti – estrogen therapy. Recalling the long term treatment of anti – estrogen in patient with estrogen sensitive breast cancer, the combination with naturally occurring phytochemical from Sweet wormwood, Artemisinins will benefit patients from lowering the systemic exposure of anti – estrogens side effects.
Written by Dr. Benz Napoli