Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.

Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?

Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of...

Bioavailability of curcumin: problems and promises.

Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF- κB, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies. Curcumin, derived from turmeric (vernacular name: Haldi), is a rhizome of the plant Curcuma longa. The medicinal use of this plant has been documented in Ayurveda (the Indian

Anticancer potential of curcumin: preclinical and clinical studies.

https://alzheimer.neurology.ucla.edu/pubs/YangJBCcurc2005.pdf

Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo

The use of herbal medicinal products and supplements has increased tremendously over the past three decades with not less than 80% of people worldwide relying on them for some part of primary health care. Although therapies involving these agents have shown promising potential with the efficacy of a good number of herbal products clearly established, many of them remain untested and their use are either poorly monitored or not even monitored at all. The consequence of this is an inadequate knowledge of their mode of action, potential adverse reactions, contraindications and interactions with existing orthodox pharmaceuticals and functional foods to promote both safe and rational use of these agents. Since safety continues to be a major issue with the use of herbal remedies, it becomes imperative, therefore, that relevant regulatory authorities put in place appropriate measures to protect public health by ensuring that all herbal medicines are safe and of suitable quality. This review discusses toxicity related-issues and major safety concerns arising from the use of herbal medicinal products and also highlights some important challenges associated with effective monitoring of their safety.

/pdf/the-growing-use-of-herbal-medicines-issues-relating-to-1ckeueyb3l.pdf

The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety

A series of novel xanthone derivatives (I) is prepared and screened for inhibitory effects on xanthine oxidase and ABTS radical-ion scavenging activity.

Antioxidant Xanthone Derivatives Induce Cell Cycle Arrest and Apoptosis and Enhance Cell Death Induced by Cisplatin in NTUB1 Cells Associated with ROS.

Over-expression of epidermal growth factor receptor (EGFR) had been correlated with poor prognosis in bladder cancer, but clinical trials using EGFR inhibitors alone in the treatment of bladder cancer did not show definite improvement. On the other hand, radiotherapy is the key element of bladder-preserving protocol for patients with muscle-invasive bladder cancer, and several preclinical data reported the advantage of combing radiation and tyrosine kinase inhibitor against EGFR. It is known that aberrantly activated signal transduction pathways can influence radiosensitivity of cancer cells. Herein, we attempt to demonstrate whether radiation can activate signal transduction pathways in bladder cancer cells, and whether the combined inhibition of such pathways can further enhance radiosensitivity. We used a RTK signaling antibody array to investigate the relative levels of phosphorylated signaling proteins. We detected that not only EGFR but also HER-2 and Akt (Ser473) were activated in T24 human bladder cancer cells after irradiation, and the phenomenon was more prominent in 10Gy dose than in 2.5Gy dose. The increased phosphorylation of EGFR and Her-2 was confirmed by Western blot. Then we performed colony formation assay of T24 and NTUB1 human bladder cancer cell lines for 7 days after treatment combining irradiation and erlotinib (an EGFR inhibitor), lapatinib (a reversible EGFR/Her-2 dual inhibitor) or afatinib (an irreversible EGFR/Her-2 dual inhibitor) in different doses. The combination index (CI) analysis revealed synergy between radiation (2.5Gy and 10 Gy) and afatinib in various doses. For T24 cells with afatinib 100nM, the CI was 0.97 in 2.5Gy and 0.66 in 10Gy. For NTUB1 cells with afatinib 100nM, the CI was 0.92 in 2.5Gy and 0.80 in 10Gy. In contrast, erlotinib or lapatinib showed only minor influence to enhance radiation effect in human bladder cancer cells. Using flow cytometry, the relative distribution of cells among various cell cycle phases were determined in cell lines treated with either DMSO, radiation 2.5Gy, afatinib 200nM, or the combination of radiation and afatinib. When compared with radiation alone, treatment combining radiation and afatinib resulted in accumulation of cells in sub-G1 phase but decrease in G2-M phase. Western blot showed the expression of cleaved poly (ADP-ribose) polymerase (PARP) was increased in the combination group when compared with radiation or afatinib alone. The results implicated that the adding of afatinib might enhance radiation effect by increasing apoptosis in bladder cancer cells. Our data clearly show that both EGFR and Her-2 signaling can be activated after radiation in human bladder cancer cells. Afatinib, an EGFR/Her-2 dual inhibitor, effectively radiosensitizes the bladder cancer cells by enhancing apoptosis. The result provides a basis for future in vivo and human studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1464. doi:1538-7445.AM2012-1464

Abstract 1464: Afatinib, an EGFR/Her-2 dual inhibitor, effectively radiosensitizes bladder cancer cells

Ten patients with prostate adenocarcinoma entered into the phase II clinical trial and treated with monthly intramuscular 3.75 mg triptorelin injection to assess its efficacy in suppressing tunmor progression and side effects. All patients were given one to three weeks of antiandrogen to inhibit the possible flare-up by the initiation of triptorelin. In results, one patient died of disseminated prostate cancer in the study period, indicating treatment failure. The other 9 patients alive after 6 to 10 months of treatment were considered as being responders by the modified Eastern Cooperative Oncology Group Tumor Response Criteria and prostate specific antigen (PSA) criteria. Of the 6 patients with measurable lesions, 5 had objective response (2 CR and 3 PR). All but the case of failure had more than 50% PSA reduction (range:90% to 100%) for 8 weeks or more. All the 9 responding patients had improvement or stabilization of the Karnofsky performance status. Of the 7 patients with complete hormonal profile checked, 5 showed significant suppression of luteinizing hormone (LH) and testosterone after 2 to 3 months of treatment. The other 2 showed no evident suppression of testosterone or LH levels, although their PSA’s declined for 90% and 100%, respectively. Only two patients had evident improvement in bone scanning as shown by the resolution of previous metastatic hot spots. All the 9 responding patients turned sexually impotent after 6 months of triptorelin treatment. One complained of hot flush, hand and foot swelling, night sweating and dizziness, which were considered as typical side effects of triptorelin as well as other forms of gonadotropin releasing hormone agonists. In conclusion, monthly triptorelin treatment is effective in suppressing prostate cancer progression and causes negligible side effects in most patients with prostate adenocarcinoma.

Phase II Clinical Trial of Monthly Triptorelin Injection for Prostate Cancer

Although prostate cancer (PC) is the most common cancer among men in the Western world, there are no good biomarkers that can reliably differentiate between potentially aggressive and indolent PC. This leads to overtreatment, even for patients who can be managed conservatively. Previous studies have suggested that nuclear lamin proteins-especially lamin B1 (LMNB1)-play important roles in PC progression. However, the results of these studies are inconsistent. Here, we transfected the LMNB1 gene into the telomerase reverse transcriptase-immortalized benign prostatic epithelial cell line, EP156T to generate a LMNB1-overexpressing EP156T (LMN-EP156T) cell line with increased cellular proliferation. However, LMN-EP156T cells could neither form colonies in soft agar, nor establish subcutaneous growth or metastasis in the xenograft NOD/SCID mouse model. In addition, immunohistochemical staining of LMNB1 in PC specimens from 143 patients showed a statistically significant trend of stronger LMNB1 staining with higher Gleason scores. A univariate analysis of the clinicopathological parameters of 85 patients with PC who underwent radical prostatectomy revealed that pathological stage, resection margin, and extracapsular extension were significant predictors for biochemical recurrence (BCR). However, LMNB1 staining showed only a non-significant trend of association with BCR (high vs. low staining: hazard ratio (HR), 1.83; 95% confidence interval (CI), 0.98-3.41; P = 0.059). In multivariate analysis, only pathological stage was a significant independent predictor of BCR (pT3 vs. pT2: HR, 2.29; 95% CI, 1.18-4.43; P = 0.014). In summary, LMNB1 may play a role in the early steps of PC progression, and additional molecular alterations may be needed to confer full malignancy potential to initiated cells.

Yeong-Shiau Pu

Papers

Antioxidant Xanthone Derivatives Induce Cell Cycle Arrest and Apoptosis and Enhance Cell Death Induced by Cisplatin in NTUB1 Cells Associated with ROS.

Abstract 1464: Afatinib, an EGFR/Her-2 dual inhibitor, effectively radiosensitizes bladder cancer cells

Phase II Clinical Trial of Monthly Triptorelin Injection for Prostate Cancer

LMNB1, a potential marker for early prostate cancer progression.

Ketoconazole in Taiwanese castration-resistant prostate cancer patients: Evaluation of response rates, durations, and predictors