Dr. Dipak K. Banerjee from the University of Puerto Rico has done an outstanding research on Breast cancer and introduced Future of the Next Generation Breast Cancer Treatment.
The breast cancer care cost in the United States tops $16.00 billion annually and is rising. It is obviously, much larger in a global scale. Breast cancer is a multi-factorial disease. Therefore, to conquer the disease many overarching challenges need to overcome. The problem with the current treatment strategies they are narrowly focused and not necessarily using multi-disciplinary approaches. In many cases, the therapeutics are targeted over and over again to the same axis of treatment while knowing fully when one pathway is blocked the cancer cell opens up another pathway. This certainly helps the pharmaceutical industries but not the patients or their families and friends who are in dire need of a cure.
Irrespective of the progress made in the area of glycoscience/glycobiology, the cancer researchers are from encashing the outcome of the discoveries. Dipak K. Banerjee’s laboratory at the University of Puerto Rico Medical School could see the gap and apply the niche to develop a glycotherapy which could serve as a next-generation therapeutic to treat breast cancer in the clinic. The group has targeted cancer holistically meaning both angiogenesis and the cancer cells received the same priorities. Using a pure protein N-glycosylation inhibitor tunicamycin Banerjee’s laboratory has categorically established that tunicamycin inhibits in vitro and in vivo angiogenesis, and the growth factors such VEGF cannot overcome the process. Also, the effect of tunicamycin cannot be washed out indicating there is a point of no return.
Similar results are obtained with nearly a half-a-dozen of human breast cancer cells. The humanized double negative and triple negative breast tumors in nude mice show a ~55%-65% reduction of tumor progression following tunicamycin treatment is given by intravenous injection or administered orally. To see a similar effect by the FDA approved breast cancer therapeutic, taxol needs 15 times more. The molecular mechanism of tunicamycin is ER stress-induced unfolded protein response (upr)-mediated apoptotic cell death. Most importantly, tunicamycin alone inhibits the pathways targeted by all current therapeutics combined. Nano-formulated tunicamycin is three times more potent than the native tunicamycin. Thus, tunicamycin is going to the least expensive glycotherapy to treat breast cancer ever known with the least amount of side effect.
Breast Cancer:
Breast cancer is a disease in which cells in the breast grow out of control. Different kinds of breast cancer include invasive ductal carcinoma; invasive lobular carcinoma; and ductal cell carcinoma in situ (DCIS) is a breast disease that may lead to breast cancer (Figure 1).
Figure 1: Breast cancer is a disease in which cells in the breast grow out of control
There are many types and sub-types of breast cancer: the most common types are estrogen Receptor positive (ER+); estrogen receptor/progesterone receptor negative and epidermal growth factor receptor-positive (double negative; ER-/PR-/HER2+); and estrogen receptor/progesterone receptor and epidermal growth factor receptor negative (triple negative; ER-/PR-/HER2-).
Statistics of Breast Cancer:
Breast Cancer incidence and mortality: Every year nearly 1.5 million women are diagnosed with breast cancer worldwide and approximately 400,000 – 500,000 women die from the disease. Breast cancer is also the second leading cause of death in women in the United States after the heart disease. In 2015, (the latest year for which incidence data are available), 242,476 new cases of Female Breast Cancer were reported, and 41,523 people died of Female Breast Cancer in the United States. This means for every 100,000 women there were 125 new Breast Cancer cases and 20 of them died from the disease. The predictions for 2018 are the following: diagnosing 266,120 new cases of invasive (15.3%) and 63,960 new cases of non-invasive (in situ) breast cancer cases with a mortality rate of 40,920 (6.7%) women.
Breast cancer incidence and deaths due to the disease vary extensively with the economic status of the countries such as the low- and middle-income countries. The percentage of death in 2014 from 94 such countries out of 114 countries presented a range as low as 0.6% to as high as 56.8%. The countries that have 1%-2% death are Bhutan (0.6%), Turkmenistan (1.2%), South Africa (1.6%), Rumania (1.7%), Somalia (1.9%) and Timor Leste (2%); and those with more than 50% deaths are Nepal (50.1%), Ukraine (50.4%), Republic of Yemen (50.5%), Guinea (53.7%), Mali (53.9%), Liberia (55.6%) and Niger (56.8%), respectively.
Who gets the disease?
Breast cancer affects women from all socio-economic status, all ethnic background, all religious beliefs, and from all national origin. The probability of a woman suffering from some form of breast cancer is 1 in 1,760 at the age 20 or below but it is 1 in 27 in the age group 61-70. Current information, however, indicates more and more women in their 30s are being diagnosed with breast cancer and that is alarming.
Breast cancer is more common among women in upper socio-economic classes, who have never been married, living in a rural area, living in the Northern United States; Lower than average rates have been recorded for Mexican-Americans, Japanese and Filipino women in Hawaii, American Indians, Seventh-Day Adventists, and Mormons; Higher-than-average risk are Jewish women, and Nuns (presumably because of their usual nulliparous status).
Minority populations are more likely to be diagnosed with advanced stage disease than are Caucasians. The rate is high in Caucasians than in African Americans for the Age 45 and over; The rates are similar for the Age 40 - 44; and the rate is higher in African Americans for Age
Warning Signs and Risk Factors of breast cancer:
The warning signs include a New lump in the breast or underarm (armpit), Thickening or swelling of part of the breast, Irritation or dimpling of breast skin, Redness or flaky skin in the nipple area or the breast, Pulling-in of the nipple or pain in the nipple area, Nipple discharge other than breast milk, including blood, Any change in the size or the shape of the breast, Pain in any area of the breast.
The risk factors for breast cancer are many. But, the most commons are: Getting older (50 years of age), Genetic mutations (BRCA1 and BRCA2 genes), Early menstrual period (before 12 years of age), Late or no pregnancy (first pregnancy after age 30), Starting menopause after age 55, Being overweight or obese after menopause, Having dense breasts, Using combination hormone therapy (taking hormones to replace estrogen and progesterone), Taking oral contraceptives (birth control pills), Personal history of breast cancer, Family history of breast cancer, Previous treatment using radiation therapy, Women who took the drug diethylstilbestrol (DES) and Drinking alcohol.
Diagnosis of Breast Cancer:
Breast cancer is currently diagnosed by Breast ultrasound (sonograms), Diagnostic mammogram (This is a more detailed X-ray of the breast), Magnetic resonance imaging (MRI; The MRI scan will make detailed pictures of areas inside the breast), Biopsy (This is a test that removes tissue or fluid from the breast to be examined under a microscope; There are different kinds of biopsies (for example, fine-needle aspiration, core biopsy, or open biopsy).
Currently Available Treatment for Breast Cancer:
Breast cancer is treated in several ways. The treatment depends on the kind of breast cancer and how far it has spread. People with breast cancer often get more than one kind of treatment such as Surgery; Chemotherapy (using special medicines to shrink or kill the cancer cells). The drugs can be pills taken orally or given intravenously, or sometimes both); Hormonal therapy (to block cancer cells from getting the hormones they need to grow. For example. tamoxifen an antagonist to estrogen receptor is used for treating ER-positive breast cancer); Biological therapy (it works with the body’s immune system to help fight cancer cells or to control side effects from other cancer treatments); Radiation therapy (it uses high-energy rays similar to X-rays to kill the cancer cells); Adjuvant therapy (these are monoclonal antibodies such as Herceptin/trastuzumab, Avastin/bevacizumab, etc.); and Complementary and Alternative Medicine (meditation, yoga, and supplements like vitamins and herbs are some examples).
Tyrosine kinase inhibitor (lapatinib); PARP inhibitors with BRCA1 or BRCA2 gene mutation; CDK4/6 inhibitor (palbociclib); PI3 kinase inhibitors; and the Immunotherapy (“checkpoint inhibitors”), etc. are being tried for metastatic breast cancer treatment. The prognosis, however, depends upon the stage at diagnosis: 5-year survival rate is 100% for Stage 0, 98% for Stage I, 88% for Stage II, 56% for Stage IIIA, 49% for Stage IIIB, and 16% for Stage IV. It is also noteworthy that many of them have severe side effects, they destroy the quality of a patient’s life, often expensive, and are not affordable to many.
What’ Next?
Key Issues: (i) Breast cancer was recognized by Egyptians as early as 1600 BC; (ii) First cancer-causing
gene in a chicken tumor virus was found in 1970; and (iii) President Richard Nixon signed
the National Cancer Act on December 23, 1971, beginning the federal government’s war on cancer.
A great deal of public and private resources have been diverted since then to find a cure for the disease. Instead of conquering the disease, breast cancer has become a major public health problem, affecting as many as one in eight women during their life time (Ries, LAG et al (1999) SEER Cancer statistics review 1973-2996. Natl. Cancer Inst., Bethesda, MD, USA; Sondik, EJ (1994) Cancer 74, 995-999). The disease is due to a progressive accumulation of mutations and chromosomal aberrations causing altered growth properties and oncogenic transformations of cells. Both endogenous and exogenous factors contribute to the development and progression of the disease [Berkowitz, GS, and Kelsey, JL (2006) Epidemiology of breast cancer. In: Diagnosis and Management of Breast Cancer (ed. Marchant DJ). Elsevier, New York]. Furthermore, the metastatic load due to epithelial-mesenchymal transition (EMT; Kalluri, R and Weinberg, RA (2009) J. Clin. Invest 119, 1420-1428) raises further complication. All these become rudimentary in the absence of neo-vascularization, i.e., angiogenesis. Angiogenesis is the proliferation of endothelial cells. As a tissue, endothelium provides an anatomical barrier between blood and intertitium. Endothelial cell proliferation and differentiation to new blood capillaries are crucial for growth and development. They however become quiescent in adults unless there is a tissue damage or a tissue growth such as cancer. In cancer, endothelial cells proliferate at a rate 45 times faster than the normal.
To approach elimination of breast cancer requires understanding that the hallmark of cancer follows the core principles of sustainability to proliferative signaling, ability to evade growth suppressors, ability to resistance cell death, ability to enable replicative immortality, angiogenesis induction, and activating invasion and metastasis. Angiogenesis, i.e., neo-vascularization is thus a “key” to breast cancer progression (Figure 2). Because of a symbiotic relationship, tumor cells
Figure 2: Tumor growth is angiogenesis dependent
turn on the “angiogenesis switch” causing endothelial cell migration from pre-existing vasculature, capillary budding, establishment of capillary loops, and finally neo-vascular remodeling Angiogenic switch” activators are tumor microenvironment; mutation in oncogenes or tumor-suppressor genes; pro-angiogenic molecules (VEGF, FGF-2, EGF, PDGF, PIGF and MMPs); and anti-angiogenic factors (thrombospondin, angiostatin, tumstatin, and endostatin [Uhr, JW et al (1997) Nat. Med. 3, 505-509; Gastl, G et al (1997) Oncology 54, 177-184].
Glycotherapy:
Breast cancer has overarching challenges so does its therapeutic strategies. The current therapeutic strategies narrowly target individual cell type (http://www.angiogenesis.org; http://cancernet.nci.nih.gov; www.clinicaltrials.gov). The Pharmaceutical Research and Manufacturers of America also report hundreds of medicines in clinical testing but many clinical trials evaluate either existing drugs in new combinations or at different stages of the disease. What remains unknown is whether the current approaches of developing more drugs and conducting more clinical trials can be redesigned to accelerate the rate of progress that will end breast cancer or the time has come to consider a paradigm shift for developing a new generation breast cancer therapeutic that can cure the disease?
Dr. Dipak K. Banerjee at the University of Puerto Rico Medical School has made two concessions while developing the “glycotherapy”, i.e., a next generation therapeutic to treat breast cancer. These are after looking at the cancer holistically (i.e., both tumor microvasculature and tumor cells) and focusing on a small molecule that will be equipotent, affordable to all and without compromising the patient’s quality of life. His target is a unique glycosyltransferase of asparagine-linked (N-linked) glycoprotein biosynthetic pathway in the endoplasmic reticulum of the cell with a 940 Dalton molecular weight sugar-containing pyrimidine nucleoside (i.e., a small molecule). It is a natural product, a biologic and a cytokine mimic.
Why targeting N-glycan pathway?
Asparagine-linked glycoprotein plays a critical role in angiogenesis and in tumor progression. Inhibition of “hybrid” and “complex”-type N-glycan synthesis inhibits the capillary tubes formation [Nguyen, M et al (1992) J. Biol. Chem. 267, 26157-26165; Nguyen, M et al (1993) Nature 365, 267-269]. Glycoprotein non-metastatic b (GPNMB) with 12 putative N-glycosylation sites also overexpresses in breast cancer including the triple negative (ER-/PR-/HER2-) breast cancer [Maric, G et al (2013) Onco Targets Ther. 6, 839-852]. Using a non-transformed capillary endothelial cell line an in vitro angiogenesis model Banerjee’s laboratory has demonstrated that cell proliferation is increased when the cells are treated with fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), PGE2, 8Br-cAMP, etc. In addition, the group has also shown that activation of cell surface β-adrenergic receptors activates N-glycan pathway and consequently increases endothelial cell proliferation by shortening the G1 phase of the cell cycle. The process is mediated by cAMP, the intracellular messenger for β-receptor signaling [Banerjee, DK et al (1985) Proc. Natl. Acad. Sci., USA 82, 4702-4706 Martinez, JA et al (1999) Cell Mol Biol (Noisy-le-grand), 45, 137-152]. Molecular analysis supports phosphorylation activation of dolichol phosphate mannose synthase (DPMS) in the endoplasmic reticulum, followed by accelerated synthesis and turnover of lipid-linked oligosaccharide (LLO) Glc3Man9GlcNAc2-PP-Dol. DPMS is an inverting GT-A folded enzyme and classified as GT2 with a conserved metal binding domain (i.e., DAD motif) and a cAMP-dependent protein phosphorylation (PKA) motif in its gene sequence. Overexpression of DPMS mimics these processes and also enhances the chemotactic behavior (i.e., migration and invasion) of the cell [Banerjee, DK et al (2017) Glycoconj J. 34, 467-479; Zang, Z et al (2010) Biocatal Biotransformation 28, 90-98]. In fact, PKA-deficient mutants isolated by classical cell genetics abrogates the DPMS activation but can be restored by in vitro phosphorylation by PKA [Banerjee, DK (2007) Cell Mol Biol (Noisy-le-grand) 53, 55-63]. Similarly, the importance of DPMS phosphorylation in cell function has further been established in yeast (S. cerevisiae) by molecular cell genetics. Replacing the phosphorylation site in DNA sequence of the DPMS gene by site-directed mutagenesis eliminates the phosphorylation activation of DPMS [Banerjee, DK et al (2005) J Biol Chem. 280, 4174-4181] and in fact, the yeast cells carrying the mutated DPMS gene exhibit retarded cell growth.
This fundamental observation has made Dr. Banerjee to conclude that increase in DPMS catalytic activity increases the activity of N-acetylglucosaminyl 1-phopsphate transferase (GPT), i.e., the existence of a cross-talk [Banerjee, DK et al (1985) Biochem Biophys Res Commun 126, 123-129; Banerjee, DK (2012) Biochim Biophys Acta 1820, 1338-1346]. An activation of GPT by dol-P-man has also been seen by others [Kean, EL (1982) J Biol Chem 257, 7952-7954]. GPT is the first enzyme of protein N-glycosylation pathway and catalyzes the transfer reaction UDP-GlcNAc + Dol-P <è GlcNAc-PP-Dol + UMP. To further delineate the DPMS-GPT cross-talk an inhibitor of DPMS catalyzed reaction is ideal but in the absence of such inhibitor, Banerjee’s laboratory became innovative and used instead a GPT inhibitor, tunicamycin. Tunicmycin (Mr840 dalton), a competitive inhibitor of GPT is a glucosamine-containing pyrimidine nucleoside and a natural product made by Streptomyces lysosuperificus. Interestingly and serendipitously, the capillary endothelial cells when treated with tunicamycin the DPMS catalytic activity is inhibited quantitatively in a time- and dose-dependent manner. The expression of DPMS protein or the DPMS gene however remains unaffected so is the processing of DPMS mRNA. It is important to note tunicamycin has no inhibitory action on DPMS catalytic activity in a test tube assay. Thus, down regulation of N-linked glycoproteins on capillary endothelial cell surface following tunicamycin treatment is expected to be due to a direct effect on GPT but the possibility of combining with DPMS cannot be ruled out.
Tunicamycin inhibits angiogenesis in vitro when tested in a somatic non-transformed capillary endothelial cell line. The effect is time and concentration dependent. Most importantly, tunicamycin inhibits only the proliferative cells. In non-proliferative cells, it behaves like a “Trojan horse”. Tunicamycin action is cell cycle specific. It causes cell cycle arrest in Go/G1 boundary and induces apoptosis in late G1. Furthermore, tunicamycin action cannot be washed out nor its inhibitory effect can be reversed by growth factors such as vascular endothelial growth factor (VEGF). In fact, tunicamycin treated cells express quantitively less phosphorylated VEGF receptor I and II. Mechanistically, tunicamycin blocks a multiple bio-signaling pathways, viz., down regulation of cyclin D/cdk signaling, IGF/AKT signaling, MAP kinase signaling, NF-κ among many others. It also upregulates p53 expression and induces autophagy. In fact, the unpublished data from Dr. Banerjee’s laboratory suggest hundreds of genes are affected which summarizes the tunicamycin treated cells has a point of no-return.
Break down of protein N-glycosylation machinery in tunicamycin treated cells causes accumulation of unfolded protein in endoplasmic reticulum (ER) and develops ER stress. The molecular signature of the ER stress is the upregulation of a glucose-regulated protein GRP78. Thus, upregulation of GRP78 expression supports unfolded protein response (upr) signaling and induction of apoptosis (i.e., programed cell death). The overwhelming evidences are DNA fragmentation, upregulation of pro-apoptotic molecules caspases-3, 9 and 12 as well as increase in intracellular free calcium ([Ca2+]i) concentration. There is attenuation of transcription (Ire1, ATF4/6) and translation (PERK) as well. Absence of cytochrome c release supports no apoptosome formation and marks the process as independent of mitochondria.
Tunicamycin when tested in Matrigel™ implants in athymic nude [Balb/c (nu/nu)] mice, macroscopic as well as H&E stained microscopic images of the Matrigel™ sections indicate absence of micro-vessels (i.e., blood capillaries). Immunohistochemistry of CD34 and CD144 expression also explain a quantitatively less number of blood vessels present in tunicamycin treated Matrigel™ sections. The protein and the mRNA expression of the endogenous anti-angiogenic factor Thrombospondin-1 (Tsp-1) on the other hand is enhanced both in tunicamycin treated Matrigel™ plugs as well as in tunicamycin treated capillary endothelial cells. The anti-angiogenic effect of tunicamycin is further supported by the decreased Matrigel™ invasion and chemotaxis of tunicamycin treated capillary endothelial cells even when VEGF is present. This confirms triggering the anti-angiogenic action of tunicamycin.
The convincing results on the inability of VEGF to reverse the anti-angiogenic effect of tunicamycin both in vitro and in vivo allow testing tunicamycin in humanized breast cancers developed in athymic nude [Balb/c (nu/nu)] mice. The study has used double-negative (ER-/PR-/HER2+) and triple-negative (ER-/PR-/HER2-) breast cancer models developed either orthotopically or as xonografts. Mice with double-negative tumor (orthotopic) have received tunicamycin through intravenous injection (iv) once a week and the mice with triple negative tumor (xenograft) have received tunicamycin orally twice a week. Control group has received vehicle only. The double-negative tumors receiving 1mg/Kg of tunicamycin regressed approximately 55% after three week whereas the triple negative tumors regressed approximately 65% after one week getting 0.25mg/Kg of tunicamycin. The FDA approved breast cancer drug taxol requires 15 times more to see a comparable effect. In the control group, the tumor growth is almost doubled in three weeks. Thus, tunicamycin treatment slows down the growth of breast adenocarcinomas. Examination of excised tumors after 23 days by H&E staining of paraffin sections of the tumor tissue indicates reduction in microvascular density with the increase in tunicamycin concentrations from zero to 1 mg/Kg. Mitotic index of tumor cells per 10 high power field (HPF) explains that the mitotic index of the tumor cells decline as a consequence of tunicamycin treatment. To correlate the tumor growth with cellular markers, expression of Ki-67 and VEGF has been analyzed immunohistochemically in tumor tissues. Ki-67 is a cellular proliferation marker and VEGF is pro-angiogenic. The breast tumor studied here is a grade III adenocarcinoma and Ki-67 or VEGF expression in tumors from tunicamycin treated group of mice (1.0 mg/kg) is reduced significantly. This paralleled the reduction of microvessel count and the mitotic index, respectively. Accumulating evidence thus supports unequivocally that tunicamycin is a dual-action glycotherapeutic. It is anti-angiogenic in one hand and kills the breast cancer cells on the hand.
Tunicamycin inhibits LLO biosynthesis and consequently the glycosylation of N-linked glycoprotein. To verify the status of the N-glycans on the breast tumor microvascular endothelial cell surface, the tissue sections are stained with Texas-Red conjugated WGA and examined under a fluorescence microscope. Tumor microvessels in untreated controls are stained markedly but the staining intensity per vessel is reduced almost 50% upon treating with tunicamycin. Tumor cells from untreated control exhibit positive WGA staining but the intensity is much less than the endothelial cells. Nevertheless, tunicamycin treatment causes a morphological change of the tumor cells, and the WGA staining is not only reduced but also appears amorphous.
Inhibition of N-glycan biosynthesis with tunicamycin develops ER stress and consequently the upr signaling (Zhang, K and Kaufman, RJ (2004) J Biol Chem, 279, 25935–25938). To evaluate whether ER stress-mediated upr exists in breast tumor microvasculature of the mice receiving tunicamycin treatment, the tumor microvascular endothelial cells are first identified by staining for CD144 (a marker for endothelial cells) and then stained for the GRP78 (an ER chaperone and the ER stress marker). In untreated control, CD144-staining of endothelium appears as a thin line around the vessel as did the GRP78 but in tumors treated with tunicamycin, a high level expression of GRP78 is evident in microvascular endothelial cells of the tumor. CD144 also stains the same area. Additionally, both CD144 and GRP78 co-localize in tumor microvasculature supporting the presence of ER stress in tumor microvasculature.
GRP78 staining in tumor cells following tunicamycin treatment also appears to be increased. To evaluate that it is not an indirect effect because of nutritional deprivation due to reduced blood flow in the tumor but due to an induction of upr in tumor cells, the effect of tunicamycin has been studied independently on human breast cancer cells. The study uses highly metastatic triple negative breast cancer cells, double negative breast cancer cells, ductal carcinoma cells, estrogen receptor positive cells as well as non-metastatic breast carcinoma cells. Tunicamycin inhibits almost quantitatively the proliferation of these cells. The effect obviously is time and dose dependent. When tested, the triple negative breast cancer cells also exhibit losing their clonogenecity. Western blotting as well as Q-PCR exhibit high expression of GRP78 in tunicamycin treated non-metastatic estrogen receptor positive as well as highly metastatic triple negative breast cancer cells indicating the presence of ER stress across all breast cancer subtypes. Mechanistic details indicate GRP78 in tunicamycin treated cancer cells is expressed in endoplasmic reticulum and not on the cell surface. Thus, supporting unfolded protein response signaling-mediate the apoptotic death of the cancer cells as well. Both in vitro and in vivo studies therefore conclude that tunicamycin is not only a novel dual-action glycotherapy for treating breast cancer but also a therapy that does not discriminate the type of breast cancer [Serrano-Negron, JE et al (2018) Glycobiology 28, 61-68; Banerjee, A et al (2011) J Biol Chem 286, 29127-29138].
To further advance the use of the glycotherapy for treating breast cancer, attention has been paid to develop a product that acts faster and has no side effect. The expectation is also to reduce the cost of the therapy and the patients treating themselves as and when needed. This leads to the development of nano-formulation of tunicamycin. These are tunicamycin encapsulated in peptide nanotubes; nanotubes bound to gold nanoparticles (Au NPs) conjugated with Tunicamycin; Tunicamycin conjugated with nanotubes; Au NPs bound to tubes and conjugated with Tunicamycin; and Au NPs conjugated with Tunicamycin. Functionalization of these nanoparticles are characterized by transmission electron microscopy (TEM), Fourier Transformed Infrared (FTIR) Spectroscopy, dynamic light scattering, atomic force microscopy (AFM), and absorbance spectroscopy. The MTT assay indicates nanoparticles (1 μg/mL) inhibits angiogenesis ~50% within one hour of treatment whereas the native tunicamycin has no effect. The nano-formulated tunicamycin blocks the cell cycle progression by inhibiting either both cyclin D1 and CDK4, or cyclin D1, or the CDK4 expression as well as the expression of phospho Rb (serine-229/threonine-252), a transcriptional co-activator. Phosphorylation of p53 at serine-392 is down-regulated but not the total p53. Increased expression of GRP-78/Bip identifies “ER stress”. Upregulated expression (1.6-5.5 fold) of phopsho-PERK and significant reduction of DPMS expression support induction of upr signaling. Down regulated expression of caspase-9 and caspase-3 proposes a non-canonical pathway of cell death during “ER stress” induced by nano-formulated tunicamycin [Banerjee, A et al (2013) Transl Cancer Res 2, 240-255).
Tunicamycin does not exert behavioral and/or skeletal toxicity in athymic nude mice. Banerjee’s study uses pure N-glycosylation inhibitor [Duksin, D and Mahoney, WC (1982) J Biol Chem 257, 3105-3109] and not the mixture of 16 different homologs of 1970s [Takatsuki, A et al (1971) J. Antibiol 24, 215-223]. The product is expected to bring down significantly the current cost of breast cancer care, which is $16.5 billion annually (Mariotto, AB et al (2011) J Natl Cancer Inst 103, 117-128).
This is not the first time Dr. Banerjee is proposing glycotherapeutic for treating diseases. As a graduate student, he proposed using autologous ß-N-acetylglucosaminyl hexosaminidase A replacement therapy for treating Tay-Sachs patients (Banerjee, DK and Basu, D (1975) Biochemical J 145, 113-118). Later on demonstrated that accumulation of disialo ganglioside in tracheal tissue is responsible for broncho constriction in hyper-reactive guinea pig model of asthmatic patients (Banerjee, DK (1982) Science 218, 569-571). His discovery of capillary endothelial cells expressing the blood clotting factor VIIIc (an asparagine-linked glycoprotein) has earned the National Institutes of Health perhaps their first US Patent. Its use could restore the normal factor VIIIc level in hemophilia A patients (Banerjee, DK et al (1985) Proc Natl Acad Sci USA 82, 4702-4706). His work on targeting the glycosylation of vesicular stomatitis G protein (an asparagine-linked glycoprotein) generates a non-infectious viral particle (Maheshwari, RK et al (1980) Nature 287, 454-456) and favors developing glycotherapy for infectious diseases including HIV-AIDS.
This research was led by Dipak K. Banerjee, Ph.D., Department of Biochemistry, School of Medicine and The Institute of Functional Nanomaterials, University of Puerto Rico, San Juan, PR 00936-5067.
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