Stopping Leukemia’s regeneration and preventing relapse

Photo Credits: Eric V. Grave / Photo Researchers, Inc., ISM/Phototake

Many cancers, and leukemia specifically, are difficult to manage because of the chance of relapse if even a tiny cancerous cell is left behind once treatment stops. Therefore, a hot topic in cancer research is the prevention of cancerous regrowth and metastasis. The ADAR1 enzyme has just been identified as a potential target to block relapse of chronic myeloid leukemia by a team bellwethered by researchers of the University of California, San Diego School of Medicine.

Chronic myeloid leukemia (CML) is a cancer of the white blood cells in which the blood forming tissue of the bone marrow (myeloid tissue) proliferates out of control and causes anemia, easy bruising, decreased ability to fend off infection, fever, and joint pain. To combat this, constant intake of tyrosine kinase inhibitors (TKIs) via chemotherapy is necessary. This works to starve the bulk of the tumor of its energy (ATP) and allow the cells to die. This method is usually long term because the TKIs do not always catch every cancerous cell. Relapse is imminent if treatment stops.

For this reason scientists looked to ADAR1.

This enzyme is expressed during very early development of the fetus to promote blood cell proliferation and protect hematopoietic stem cells from viral attack. Leukemic tumors sequester this enzyme for the protection of their own cells activating ADAR1 when it is not needed. This protects the cancerous white blood cells from chemotherapy and allows for enhanced proliferation of the cells.

Researchers performed a 50% knockdown of ADAR1 in vivo using a murine model to test the effects on CML progenitor cells. The self-renewal rate of the leukemia stem cells was reduced by about 30% by this ADAR1 knockdown test. This confirmed the enzyme’s role in the self renewal of the CML cells.

This puts ADAR1 on the table as a potential drug target for cancer treatment. ADAR1 knockdown in patients receiving tyrosine kinase inhibitors may be what is needed to  kill myeloid leukemia tumors, stop its regeneration, and eradicate the disease from the body for good without the need for perpetual treatment.

Combination treatments get another thumbs up from me if we see this therapy in the clinic soon.

Qingfei Jiang, Leslie A. Crews, Christian L. Barrett, Hye-Jung Chun, Angela C. Court,
Jane M. Isquith, Maria A. Zipeto, Daniel J. Goff, Mark Minden, Anil Sadarangani,
Jessica M. Rusert, Kim-Hien T. Dao, Sheldon R. Morris, Lawrence S. B. Goldstein, Marco A. Marra, Kelly A. Frazer, Catriona H. M. Jamieson. ADAR1 promotes malignant progenitor reprogramming
in chronic myeloid leukemia. PNAS, 2012.


Lower vitamin-D, higher breast cancer risk

Photo credits: Jacek Chabraszewski

No woman ever wants to hear the words “You have breast cancer,” but what if the same woman was told “Breast cancer may develop soon.” instead? Would she be as heart broken? Researchers of the University of California, San Diego (Yea, I spelled out UCSD..waddup?), SDSU, and Heartland Assays (Iowa) discovered that low detectable levels of vitamin D are closely linked with risk of developing breast cancer in young women.

The group found that women who had low serum 25-hydroxyvitamin-D (25(OH)D) three months prior to diagnosis had lower levels of vitamin-D that correlated with their risk of breast cancer. Varied levels prior to this three month period showed no significant link to risk of breast cancer.

25(OH)D is the broken down form of Vitamin D3 that physicians measure for in the blood when detecting vitamin-D concentration.

Vitamin D deficiency has an increasing prevalence in the U.S. as sunscreens with high levels of protection become more popular. Everyday use of such protection blocks UVB, which is needed to make vitamin-D in the body. For this reason, the risk of developing vitamin-D deficiency is higher in late summer/early fall/winter. However, that tangent was just a small aside.

Vitamin-D deficiency has been linked to other types of cancer such as prostate. For this reason, the current study was executed to ascertain the possible link between serum 25(OH)D levels and breast cancer risk.

600 women with breast cancer were matched to 600 control women without breast cancer for this case-control retrospective study. In analysis of 25(OH)D levels of all women, those in the lowest quintile (Q1) of concentration had a three times greater risk of developing breast cancer (Odds ratio: 3.3) than those in the highest quintile (Q5) (Odds ratio: 1.0, p trend = 0.09). However, this association was only seen when levels were low at most 90 days prior to diagnosis.

Because low concentrations showed no significant link greater than 90 days prior to diagnosis, perhaps the tumor is sequestering vitamin-D rapidly during its initial growth. The mechanism of interaction between vitamin D and breast cancer is currently unknown, but further research may reveal a causal relationship between the two. Vitamin-D may be a link to breast cancer prevention, further studies will tell.

For now, this study shows that low pre-diagnostic levels of vitamin-D are significantly associated with higher risk of breast cancer. Abnormal drops in vitamin-D levels may be usable in early detection of breast cancer.

Sharif B. Mohr, Edward D. Gorham, John E. Alcaraz, Christopher I. Kane, Caroline A. Macera, J. Kellogg Parsons, Deborah L. Wingard, Ronald Horst, Cedric F. Garland. Serum 25-hydroxyvitamin D and breast cancer in the military: a case–control study utilizing pre-diagnostic serum. Cancer Causes and Control, 2013.

Liver Cancer’s worst nightmare, Docosahexaenoic acid

Human liver. Photo credits: HealthHabbits

Human liver.
Photo credits: HealthHabbits

Hepatocellular carcinoma (HCC) or liver cancer might have finally been met with an agent that blocks its growth and isn’t harmful to human health. Docosahexaenoic acid (DHA), an ω-3 fatty acid, was used by researchers of Anhui Province, China to stop the migration of and induce apoptosis in hepatocellular carcinoma cells.

Epidemiologically, liver cell cancer usually affects more men than women, those over the age of 50, and people in Asia and Africa and is usually caused by alcohol abuse, chronic liver inflammation, or hepatitis B/C infection.

Omega (ω) 3 fatty acids are commonly found in fish oils and known to have beneficial effects for the body. An example is the incidence of breast cancer being four to five times higher in western countries than in Japan, a country that eats much more seafood daily than the west. DHA specifically was used in this study to test the effects of ω-3 polyunsaturated fatty acids on HCC and search for the mechanism of action.

HCC cells were cultured then treated with varying levels of DHA for 72 hours. Using between 25 and 200 µmol/L DHA an increasing trend of decreased cell density was seen between time 0 and 72 hours.(so, less cells with more DHA and time). After treating HCC cell cultures for 72 hours with 200 µmol/L DHA the following was seen:

– Just over 20% of cancer cells survived
– An over 30 fold increase in apoptosis (cell suicide) was seen

The pathway behind the significant increase in cell apoptosis was attributed to modified activity of the Bim gene, Bcl-2 protein, Bax protein, and caspase-3 protein effector. Bcl-2 and Bim, two factors that protect cells against apoptosis, both showed decreased activity with increasing DHA. Also, caspase-3 and Bax, two pro-apoptotic factors, showed increased activity.

Finally, a scratch wound assay testing how quickly HCC cells migrated to the wound in the presence/absence of DHA showed blunted migration of cells when DHA was included. Immunofluorescence showed decreased MMP-9, a protein required for HCC cell migration, levels based on DHA concentration.

Wrapping all together, the modified Bim, Bcl-2, caspase-3, and Bax levels showing increased apoptosis, decreased MMP-9 levels indicating less cell migration, and overall decreased cell density seen with more DHA used yields significant evidence for DHA being effective in stopping liver cancer.

Since DHA is an ω-3 and essential fatty acid, it may be a shorter task to move it into the clinic as a treatment for hepatocellular carcinoma.

Si-Nan Sun, Wei-Dong Jia, Hao Chen, Jin-Liang Ma, Yong-Sheng Ge, Ji-Hai Yu, Jian-Sheng Li. Docosahexaenoic acid (DHA) induces apoptosis in human hepatocellular carcinoma cells. International Journal of Clinical and Experimental Pathology, 2013.