Tea phytochemicals for breast cancer prevention and intervention: From bench to bedside and beyond.

The National Cancer Institute of the United States had projected breast cancer as one of the topmost prevalent malignancies of 2016. It was estimated that in 2016, 246,660 new cases of invasive breast cancer were expected to be diagnosed in women in the US, along with 61,000 new cases of non-invasive (in situ) breast cancer. The heterogeneity of breast cancer accounts for its differential molecular subtyping. Recent incorporation of high throughput approaches helps early prognosis of breast cancer, but recurrence of the disease stands to be one of the most daunting fact behind non-availability of third line treatment. At this point of crisis, application of chemopreventive measures could possibly resolve the enigma of breast cancer. The world class beverage tea has proven its efficacy in ameliorating various genetic and epigenetic anomalies in breast cancer. Tea phytoconstituents are known to modulate myriad molecular events which include prominent regulators of intracellular signaling, such as phosphatidylinositide 3-kinase/protein kinase B/nuclear factor-κB, epidermal growth factor receptor, vascular endothelial growth factor, B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein in the development and progression of breast carcinoma. This review aims to encompass the detailed modulatory roles of tea phytochemicals, their analogs and nanoformulations against mammary carcinoma and the probability of using tea in therapeutic management of breast cancer. Finally, current limitations, challenges and future directions of tea and breast cancer research are also critically discussed.

Chemoprotective and chemosensitizing properties of selenium nanoparticle (Nano-Se) during adjuvant therapy with cyclophosphamide in tumor-bearing mice.

Cyclophosphamide (CP) is one of the widely used anticancer agents; however, it has serious deleterious effects on normal host cells due to its nonspecific action. The essential trace element Selenium (Se) is suggested to have chemopreventive and chemotherapeutic efficacy and currently used in pharmaceutical formulations. Previous report had shown Nano-Se could protect CP-induced hepatotoxicity and genotoxicity in normal Swiss albino mice; however, its role in cancer management is still not clear. The aim of present study is to investigate the chemoprotective efficacy of Nano-Se against CP-induced toxicity as well as its chemoenhancing capability when used along with CP in Swiss albino mice against Ehrlich's ascites carcinoma (EAC) cells. CP was administered (25 mg/kg b.w., i.p.) and Nano-Se was given (2 mg Se/kg b.w., p.o.) in concomitant and pretreatment schedule. Increase levels of serum hepatic marker, hepatic lipid peroxidation, DNA damage, and chromosomal aberration in CP-treated mice were significantly (P < 0.05) reversed by Nano-Se. The lowered status of various antioxidant enzymes in tumor-bearing mice after CP treatment was also effectively increased by Nano-Se. Administration of Nano-Se along with CP caused a significant reduction in tumor volume, packed cell volume, viable tumor cell count, and increased the survivability of the tumor-bearing hosts. The results suggest that Nano-Se exhibits significant antitumor and antioxidant effects in EAC-bearing mice. The potential for Nano-Se to ameliorate the CP-evoked toxicity as well as to improve the chemotherapeutic effect could have beneficial implications for patients undergoing chemotherapy with CP.

Resveratrol for breast cancer prevention and therapy: Preclinical evidence and molecular mechanisms.

Globally, breast cancer is the most frequently diagnosed cancer among women. The major unresolved problems with metastatic breast cancer is recurrence after receiving objective response to chemotherapy, drug-induced side effects of first line chemotherapy and delayed response to second line of treatment. Unfortunately, very few options are available as third line treatment. It is clear that under such circumstances there is an urgent need for new and effective drugs. Phytochemicals are among the most promising chemopreventive treatment options for the management of cancer. Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a non-flavonoid polyphenol present in several dietary sources, including grapes, berries, soy beans, pomegranate and peanuts, has been shown to possess a wide range of health benefits through its effect on a plethora of molecular targets.The present review encompasses the role of resveratrol and its natural/synthetic analogue in the light of their efficacy against tumor cell proliferation, metastasis, epigenetic alterations and for induction of apoptosis as well as sensitization toward chemotherapeutic drugs in various in vitro and in vivo models of breast cancer. The roles of resveratrol as a phytoestrogen, an aromatase inhibitor and in stem cell therapy as well as adjuvent treatment are also discussed. This review explores the full potential of resveratrol in breast cancer prevention and treatment with current limitations, challenges and future directions of research.

Nano-Se attenuates cyclophosphamide-induced pulmonary injury through modulation of oxidative stress and DNA damage in Swiss albino mice.

Chemotherapy is an integral part of modern day treatment regimen but anticancer drugs fail to demarcate between cancerous and normal cells thereby causing severe form of systemic toxicity. Among which pulmonary toxicity is a dreadful complication developed in cancer patients upon cyclophosphamide (CP) therapy. Oxidative stress, fibrosis, and apoptosis are the major patho-mechanisms involved in CP-induced pulmonary toxicity. In the present study, we have synthesized Nano-Se, nanotechnology-based new form of elemental selenium which has significantly lower toxicity and acceptable bioavailability. In order to meet the need of effective drugs against CP-induced adverse effects, nano selenium (Nano-Se) was tested for its possible protective efficacy on CP-induced pulmonary toxicity and bone marrow toxicity. CP intoxication resulted in structural and functional lung impairment which was revealed by massive histopathological changes. Lung injury was associated with oxidative stress/lipid peroxidation as evident by increased in reactive oxygen species, nitric oxide level, and malondialdehyde (MDA) formation with decreased in level of antioxidants such as reduced glutathione, glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, and catalase. Furthermore, CP at a dose of 25 mg/kg b.w. increased pulmonary DNA damage ('comet tail') and triggered DNA fragmentation and apoptosis in mouse bone marrow cells. On the other hand, Nano-Se at a dose of 2 mg Se/kg b.w., significantly inhibited CP-induced DNA damage in bronchoalveolar lavage cells, and decreased the apoptosis and percentage of DNA fragmentation in bone marrow cells and also antagonized the reduction of the activities of antioxidant enzymes and the increase level of MDA. Thus, our results suggest that Nano-Se in pre- and co-administration may serve as a promising preventive strategy against CP-induced pulmonary toxicity.

In search of natural remediation for cervical cancer.

Cancer is a serious global health issue. Cancer of the cervix is one of the leading gynecological malignancies worldwide; though it is more prevalent in the developing countries. Fruitful approaches are needed to control cervical cancer. Awareness through proper education, screening and early detection may pave a way to combat the disease process in the first place. Surgery, chemotherapy and radiotherapy are some of the common modes of treatment for cervical cancer. Conventional medical treatments often are not able to eliminate the offending growth fully and are not free from complications. Side effects very often are disastrous. Therefore, it is high time to focus our attention to bring about a novel way to tackle the problem. Advocating holistic approach using plant derived phytochemicals may address this health problem. These molecules show potent anticancer potential and are free from toxicity. Adjunctive therapies using phytochemicals may prove to be of tremendous importance. Plants are a prime source of effective drugs for the treatment of various forms of cancer. Many of these compounds are well characterized and have led the researchers to develop potential chemotherapeutic agents. Neutraceuticals may not replace the conventional treatment regimen, but they may enhance the efficacy of chemotherapy and radiotherapy.

Clearance of cervical human papillomavirus infection by topical application of curcumin and curcumin containing polyherbal cream: a phase II randomized controlled study.

Curcumin and curcumin containing polyherbal preparations have demonstrated anti-microbial and anti- viral properties in pre-clinical studies. Till date no therapeutic intervention has been proved to be effective and safe in clearing established cervical human papillomavirus (HPV) infection. The present study evaluated the efficacy of Basant polyherbal vaginal cream (containing extracts of curcumin, reetha, amla and aloe vera) and of curcumin vaginal capsules to eliminate HPV infection from cervix. Women were screened by Pap smear and HPV DNA test by PCR. HPV positive women without high grade cervical neoplasias (N=287) were randomized to four intervention arms to be treated with vaginal Basant cream, vaginal placebo cream, curcumin vaginal capsules and placebo vaginal capsules respectively. All subjects were instructed to use one application of the assigned formulation daily for 30 consecutive days except during menstruation and recalled within seven days of the last application for repeat HPV test, cytology and colposcopy. HPV clearance rate in Basant arm (87.7%) was significantly higher than the combined placebo arms (73.3%). Curcumin caused higher rate of clearance (81.3%) than placebo though the difference was not statistically significant. Vaginal irritation and itching, mostly mild to moderate, was significantly higher after Basant application. No serious adverse events were noted.

Neem leaf glycoprotein overcomes indoleamine 2,3 dioxygenase mediated tolerance in dendritic cells by attenuating hyperactive regulatory T cells in cervical cancer stage IIIB patients.

Tolerogenic dendritic cells (DCs) are a subset of DCs characterized by abundant indoleamine 2,3 dioxygenase (IDO) expressions. IDO may be co-operatively induced in DCs by regulatory T (Tregs) cells and various DC maturation agents. Tregs are markedly amplified in the physiological system of cancer patients, inducing over tolerance in DCs that leads to the hyper accumulation of immunosuppressive IDO in tumor microenvironment, thereby, hampering anti-tumor immunity. Consequently, a major focus of current immunotherapeutic strategies in cancer is to minimize IDO, which is possible by reducing Tregs and using various IDO inhibitors. Neem leaf glycoprotein (NLGP), a natural and nontoxic immunomodulator, demonstrated several unique immunoregulatory activities. Noteworthy activities of NLGP are to mature DCs and to inhibit Tregs. As Tregs are inducer of IDO in DCs and hyperactive Tregs is a hallmark of cancer, we anticipated that NLGP might abrogate IDO induction in DCs by inhibiting Tregs. Evidences are presented here that in a co-culture of DCs and Tregs isolated from cervical cancer stage IIIB (CaCx-IIIB) patients, NLGP does inhibit IDO induction in DCs by curtailing the over expression of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) on Tregs and concomitantly induces optimal DC maturation. In contrast, in the presence of LPS as maturation agent the DCs displays a tolerogenic profile. This finding suggests the reduction of tolerogenecity of DCs in CaCx-IIIB patients by reducing the IDO pool using NLGP. Accordingly, this study sheds more light on the diverse immunomodulatory repertoire of NLGP.

Chemopreventive and chemotherapeutic potential of curcumin in breast cancer.

Breast cancer remains the leading cause of cancer death among females worldwide. It signifies a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Current treatment modalities, including surgery, radiotherapy, and adjuvant chemotherapy or hormone therapy, have not been successful enough to impart significant improvement in the morbidity or mortality of breast cancer. This cancer is highly resistant to chemotherapy as no effective treatment exists for advanced disease conditions. Moreover, there is a dearth of ideal protein biomarkers of breast cancer in plasma or serum that can be used with desired sensitivity and specificity. Along with the existing therapeutic modalities of breast cancer the focus of researchers and clinicians have shifted towards the exploration of the preventive and therapeutic uses of natural products, including dietary phytoconstituents. Curcumin, the principal active component of Indian curry spice turmeric, has been found to exert preventive and therapeutic effects in various cancers. This is, in part, due to its ability to influence a diverse range of molecular targets and signaling pathways. The ability of curcumin to enhance the efficacy of existing chemotherapeutic agents is an added advantage. The current review critically analyzes various aspects of curcumin-related research conducted for molecular understanding of its efficacy in in vitro and in vivo models of breast cancer. The article also highlights recent developments with synthetic analogs of curcumin and nanocurcumin which are in the horizon of next generation targeted therapy with curcumin in breast cancer.

A homeopathic approach to treat patients with advanced gallbladder, periampullary, and liver carcinomas: a report of 3 cases.

OBJECTIVES: The authors present 3 cases of various pathologically confirmed malignancies (one gallbladder, one periampullary, and one liver). These patients underwent Psorinum therapy as the primary cancer treatment. Psorinum therapy is a homeopathic approach to treat patients with cancer. SUBJECTS: According to the American Joint Committee on Cancer tumor, nodes, metastasis system, all 3 patients were diagnosed at Stage IV. Their Karnofsky performance status was between 20% and 50% and their Eastern Cooperative Oncology Group score status was between 3 and 4. In these cases, conventional cancer treatments could not be initiated due to the advanced stage of their disease, poor general health performance status, and their financial constraints. INTERVENTIONS AND OUTCOME: In these patients, Psorinum-6x was administered orally at a dose of 0.02 mL/kg body weight/day on an empty stomach for a complete course duration of 2 years, along with allopathic and homeopathic supportive treatment. According to the Response Evaluation Criteria in Solid Tumors criteria, complete tumor response occurred in 1 case and partial tumor response occurred in the other 2 cases. All 3 patients remained alive and maintained a stable quality of life for at least 2 years. The patients reported no adverse side-effects from Psorinum-6x. CONCLUSIONS: This report indicates the clinical efficacy of Psorinum therapy in treating those 3 patients. Thorough basic research and well-designed clinical trials should be conducted for further investigation of this homeopathic cancer treatment in order to integrate it into the mainstream of oncology treatments.

Curcumin prevents DNA damage and enhances the repair potential in a chronically arsenic-exposed human population in West Bengal, India.

Induction of oxidative stress and inhibition of DNA repair are possible modes of arsenic-induced carcinogenesis. In West Bengal, India, several districts contain high levels of arsenic, which are far above the WHO-recommended standard. Prevention of arsenic-induced oxidative stress and induction of repair enzymes by curcumin, an active ingredient of turmeric, may be an effective strategy to combat the adverse effects of arsenic. This study aimed at observing the role of curcumin in reducing 8-hydroxy-20-deoxyguanosine formation and enhancing DNA repair capacity in the arsenic-exposed population of West Bengal. Chronically arsenic-exposed volunteers (n= 66), who were asymptomatic, were selected for this study. Our results indicated that curcumin suppressed the 8-hydroxy-20-deoxyguanosine level and OGG1 expression, which were increased by arsenic. Curcumin also induced DNA repair enzymes involved in both base excision repair and nonhomologous end-joining pathways. In this study, both the protein expression and genetic profile were observed for poly-ADP-ribose polymerase 1, DNA b polymerase, X ray repair cross complement 1, DNA ligase III, DNA protein kinase catalytic sub-unit, X ray repair cross-complement 4, DNA ligase IV, and topoisomerase II b. The results indicated that arsenic-inhibited DNA repair was induced by curcumin, both at protein and genetic levels. Thus, curcumin intervention may be a useful modality for the prevention of arsenic-induced carcinogenesis.

Psorinum therapy in treating stomach, gall bladder, pancreatic, and liver cancers: a prospective clinical study.

We prospectively studied the clinical efficacy of an alternative cancer treatment "Psorinum Therapy" in treating stomach, gall bladder, pancreatic and liver cancers. Our study was observational, open level and single arm. The participants' eligibility criteria included histopathology/cytopathology confirmation of malignancy, inoperable tumor, and no prior chemotherapy or radiation therapy. The primary outcome measures of the study were (i) to assess the radiological tumor response (ii) to find out how many participants survived at least 1 year, 2 years, 3 years, 4 years and finally 5 years after the beginning of the study considering each type of cancer. Psorinum-6x was administered orally to all the participants up to 0.02 ml/Kg body weight as a single dose in empty stomach per day for 2 years along with allopathic and homeopathic supportive cares. 158 participants (42 of stomach, 40 of gall bladder, 44 of pancreatic, 32 of liver) were included in the final analysis of the study. Complete tumor response occurred in 28 (17.72%) cases and partial tumor response occurred in 56 (35.44%) cases. Double-blind randomized controlled clinical trial should be conducted for further scientific exploration of this alternative cancer treatment.

Naphthalimide based novel organoselenocyanates: finding less toxic forms of selenium that would retain protective efficacy.

A series of naphthalimide based organoselenocyanates were synthesized and screened for their toxicity as well as their ability to modulate several detoxifying/antioxidative enzyme levels at a primary screening dose of 3 mg/kg b.w. in normal Swiss albino mice for 30 days. Compound 4d showed highest activity in elevating the detoxifying/antioxidant enzymes levels.

Indian spice curcumin may be an effective strategy to combat the genotoxicity of arsenic in Swiss albino mice.

Inorganic arsenic (As) is considered as a human carcinogen because it is associated with cancers of skin, lung, liver and bladder in exposed population. Consumption of As contaminated ground water for long term causes oxidative stress. Generation of reactive oxygen species (ROS), beyond the body's endogenous antioxidant balance results severe imbalance of the cellular antioxidant defense mechanism. The present study was conducted to investigate the antioxidative effect of curcumin against sodium arsenite (As III) induced oxidative damage in Swiss albino mice. Bio-monitoring with comet assay and micronucleus assay revealed that the increase in genotoxicity caused by As III was counteracted when mice were orally administered with 5, 10 and 15 mg curcumin kg-1 bw (body weight) daily. ROS generation, lipid peroxidation and protein carbonyl content, which were elevated by As III, were reduced when treated with curcumin. Curcumin also exhibited protective action against the As III induced depletion of antioxidants like catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST) and glutathione (GSH) in mice liver tissue. Thus the present work provides a direct evidence for the involvement of curcumin in reducing As III induced oxidative stress in Swiss albino mice by virtue of its antioxidant potential and trapping of free radicals.

Curcumin protects DNA damage in a chronically arsenic-exposed population of West Bengal.

Groundwater arsenic contamination has been a health hazard for West Bengal, India. Oxidative stress to DNA is recognized as an underlying mechanism of arsenic carcinogenicity. A phytochemical, curcumin, from turmeric appears to be potent antioxidant and antimutagenic agent. DNA damage prevention with curcumin could be an effective strategy to combat arsenic toxicity. This field trial in Chakdah block of West Bengal evaluated the role of curcumin against the genotoxic effects of arsenic. DNA damage in human lymphocytes was assessed by comet assay and fluorescence-activated DNA unwinding assay. Curcumin was analyzed in blood by high performance liquid chromatography (HPLC). Arsenic induced oxidative stress and elucidation of the antagonistic role of curcumin was done by observation on reactive oxygen species (ROS) generation, lipid peroxidation and protein carbonyl. Antioxidant enzymes like catalase, superoxide dismutase, glutathione reductase, glutathioneS-transferase, glutathione peroxidase and non-enzymatic glutathione were also analyzed. The blood samples of the endemic regions showed severe DNA damage with increased levels of ROS and lipid peroxidation. The antioxidants were found with depleted activity. Three months curcumin intervention reduced the DNA damage, retarded ROS generation and lipid peroxidation and raised the level of antioxidant activity. Thus curcumin may have some protective role against the DNA damage caused by arsenic.