A colon cancer cell isn’t a lost cause. Vitamin D can tame the rogue cell by adjusting everything from its gene expression to its cytoskeleton. In the Nov. 17 issue of the Journal of Cell Biology, Ordóñez-Morán et al. show that one pathway governs the vitamin’s diverse effects. The results help clarify the actions of a molecule that is undergoing clinical trials as a cancer therapy.

Vitamin D stymies colon cancer cells in two ways. It switches on genes such as the one that encodes E-cadherin, a component of the adherens junctions that anchor cells in epithelial layers. The vitamin also induces effects on the cytoskeleton that are required for gene regulation and short-circuiting the Wnt/b-catenin pathway, which is overactive in most colon tumors. The net result is to curb division and prod colon cancer cells to differentiate into epithelial cells that settle down instead of spreading.

To delve into the mechanism, the team dosed colon cancer cells with calcitriol, the metabolically active version of vitamin D. Calcitriol triggered a surge of calcium into the cells and the subsequent switching on of RhoA–RhoGTPases, which have been implicated in the cytoskeletal changes induced by vitamin D. The activated RhoA in turn switched on one of its targets, the rho-associated coiled kinase (ROCK), which then roused two other kinases. Each step in this nongenomic pathway was necessary to spur the genomic responses, the researchers showed. The team also nailed down the contribution of the vitamin D receptor (VDR). The receptor was crucial at the beginning of the pathway, where it permitted the calcium influx, and at the end, where it activated and repressed genes.

The study is the first to show that vitamin D’s genomic and nongenomic effects integrate to regulate cell physiology. One question the researchers now want to pursue is whether VDR from different locations—the nucleus, the cytosol, and possibly the cell membrane—has different functions in the pathway.

###

Ordóñez-Morán, P., et al. 2008. J. Cell Biol. doi:10.1083/jcb.200803020.

Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Can Res. 2008;14(14): 4491-4499.

Pancreatic cancer is almost always lethal, and most patients die within 1 year of diagnosis. The only drugs approved by the Food and Drug Administration that are currently available for treatment are gemcitabine and erlotinib. Both of these drugs elicit responses in only a small percentage of patients (less than 10%), and their effect on survival is measured in weeks. Thus, effective treatments are urgently needed. Many studies have shown that nuclear transcription factor-kB (NF-kB) is activated in patients with pancreatic cancer; therefore, an agent that targets NF-kB may prove effective in the treatment of this disease. Previous laboratory research has shown that curcuminoids, a group of compounds derived from turmeric (Curcuma longa, Zingiberaceae), i.e. curcumin, desmethoxy curcumin and bisdesmethoxycurcumin, suppress NF-kB activation, cell growth associated with apoptosis (programmed cell death), and the growth of human pancreatic cancer xenografts in mice. Phase I human clinical trials of curcuminoids have shown that curcuminoids are safe at doses up to 8 g/day but that their oral bioavailability may be poor. Thus, this phase II clinical trial was undertaken to determine whether orally administered curcuminoids have biological activity in patients with advanced pancreatic cancer.

 Twenty-five patients (13 men, 12 women; aged 43-77) with histologically confirmed pancreatic cancer and a Karnofsky performance score greater than 60 were enrolled in this nonrandomized, open-label, phase II trial, which was conducted at the University of Texas M. D. Anderson Cancer Center in Houston, Texas (n = 48–62, depending on the cytokine measured) were enrolled as controls. The patients ingested 8 g of curcuminoids in capsule form (1 capsule = 1 g curcuminoids [900 mg curcumin, 80 mg desmethoxycurcumin, and 20 mg bisdesmethoxycurcumin]; provided by Sabinsa Corp., Piscataway, New Jersey) daily. Concomitant chemotherapy or radiotherapy was prohibited, but supportive care was allowed. Disease staging, a physical examination, and blood sampling were performed at baseline and at 4 and 8 weeks. Blood samples were used to measure the following values: cytokine concentrations (interleukin-6, -8, -10, and interleukin-1 receptor antagonist), carcinoembryonic antigen concentrations, and peripheral blood mononuclear cell expression of NF-kB and cyclooxygenase-2 (COX-2). The adverse events were assessed on the basis of the National Cancer Institute Expanded Common Toxicity Criteria (http://ctep.cancer.gov/forms/CTCAEv3.pdf), and tumor response was evaluated on the basis of the Response Evaluation Criteria in Solid Tumors.

 Twenty-four patients were available for the toxicity evaluation, and 21 patients were available for evaluation of the response to treatment with curcuminoids. Circulating concentrations of curcumin in blood serum were low, which indicated poor oral bioavailability. However, 2 patients exhibited a favorable response to curcuminoids. Pancreatic cancer remained stable in 1 of these patients for greater than 18 months. “Marked” tumor regression (73%) and significant (P < 0.05) increases in serum interleukin-6, -8, and -10 and in interleukin-1 receptor agonist were observed in the other patient. NF-kB activation decreased with curcuminoids treatment, but not significantly compared with the healthy controls. COX-2 expression decreased significantly (P < 0.03) with curcumin treatment. Blood concentrations of curcumin peaked at 22–41 ng/mL and remained relatively constant over the first 4 weeks of the study. Carcinoembryonic antigen concentrations decreased gradually over 1 year in 1 patient, which indicated an improvement in cancer status. No treatment-related toxicity was observed.

 The results of this study indicate that oral curcuminoids is tolerated well at doses of 8 g/d for up to 18 months and “has biological activity in some patients with pancreatic cancer.” Although curcumin was poorly absorbed, biological activity (i.e., tumor regression and increase in cytokine concentrations) was evident at steady-state. Because curcumin is hydrophobic (i.e., not water soluble), it cannot be administered intravenously unless encapsulated in a liposome, which would presumably result in higher circulating concentrations of curcumin. The authors intend to conduct clinical trials in pancreatic cancer patients with the use of liposomal curcuminoids, which they hope will result in more consistent blood concentrations of curcumin and a better pharmacologic effect.

Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Agggarwal BB. Curcumin and cancer: An “old-age” disease with an “age-old” solution. Cancer Lett. 2008 Aug 18;267(1): 133-164.

According to studies, say the authors, only 5-10% of cancers are caused by genetic factors; the remainder are caused by lifestyle. The authors call cancer a disease of “old age” because of an estimated incubation time of 20 to 30 years. And, although cancers are characterized by the dysregulation of cell-signaling pathways at multiple steps, most current anticancer therapies are single-target therapies. Many plant-based products, however, are naturally multitargeting, and, in addition, are inexpensive and safe compared with synthetic agents. The authors present a systematic review of the clinical and experimental data on the use of curcumin, a plant-based product, in the treatment of cancer.

Curcumin is the principal curcuminoid of turmeric (Curcuma longa). Chemically, it is a bis-α,β-unsaturated β-diketone, having a predominant keto form in acidic and neutral solutions and a stable enol form in alkaline media. Commercial curcumin is a mixture of curcuminoids, containing approximately 77% diferuloylmethane, 18% demothoxycurcumin, and 5% bisdemethoxycurcumin.

 Important to its therapeutic potential against cancer is curcumin’s ability to modulate numerous targets and multiple cellular signaling pathways (as demonstrated in the many studies cited in this review), including:

• Cell cycle (cyclin D1 and cyclin E),

• Apoptosis (activation of caspases and down-regulation of antiapoptotic gene products),

• Proliferation (human epidermal growth factor receptor [HER-2], epidermal growth factor-receptor [EGFR], and activator protein-1 [AP-1]),

• Survival (P12K/AKT pathway),

• Invasion (matrix metalloproteinase-9 [MMP-9] and adhesion molecules),

• Angiogenesis (vascular endothelial growth factor [VEGF]), and

• Metastasis (CXCR-4 and 5-lipoxygenase [5-LOX]).

Breast Cancer

Several reports have described the anticarcinogenic activity of curcumin in various breast cancer cell lines. The authors describe the several mechanisms that have been proposed to account for the action of curcumin in breast cancer cells. In addition, they cite several in vivo studies which have shown an association between curcumin and reduced incidence of mammary tumors in rats and reduced metastasis of the disease. In an early clinical trial cited, 71% of seven patients with breast cancer using a topical application of a curcumin ointment showed reduction in lesion size, pain, itching, and exudates.

 Gastrointestinal Cancers

Few studies have examined curcumin as a potential candidate for use in the treatment of esophageal cancer, and no in vitro evaluation of its effects in esophageal cancer cells has been reported. The authors cite two in vivo studies.

 The authors also cite in vivo studies of the use of curcumin in gastric, intestinal, hepatic, pancreatic, and colorectal cancers. In a phase I clinical trial, six patients with intestinal metaplasia of the stomach were treated with curcumin for three months. One out of the six patients showed histologic improvement in precancerous lesions after the treatment.

 Genitourinary Cancers

Numerous reports indicate that curcumin is active against bladder cancer. A phase I clinical trial in patients with resected bladder cancer reported that up to 12 g per day of curcumin for three months is pharmacologically safe, and the investigators also noted an indication of histologic improvement of precancerous lesions in one out of two patients. Curcumin has been shown to have apoptotic and antiproliferative effects against renal cell adenocarcinoma in vitro and in vivo. It has also shown activity against various prostate cancer cells. The authors cite several in vivo studies of the anticancer potential of curcumin against prostate cancer. In a clinical trial, a patient was treated with Zyflamend® (New Chapter Inc, Brattleboro, VT), an herbal preparation containing curcumin, for 18 months against high-grade prostatic intraepithelial neoplasia (HGPIN). After six months, the biopsy revealed benign prostatic hyperplasia alone, and after 18 months, biopsy was negative for cancer and PIN.

 The authors cite in vivo studies of curcumin and cervical, ovarian, and uterine cancers. In a phase I clinical trial, a daily 0.5-12 g dose of curcumin taken orally for three months resulted in the histologic improvement of precancerous lesions in one out of four patients with uterine cervical intraepithelial neoplasms. Regarding ovarian cancer, the authors describe one of their studies that demonstrated that curcumin had therapeutic and chemosensitization effects and reversed multidrug resistance both in vitro and in vivo in athymic mice.

Very few studies on the anticancer activity of curcumin against uterine cancer have been reported. The authors cite one in vitro study.

Thoracic/Head and Neck Cancers

The authors cite studies of curcumin’s anticancer effects in various lung cancer cells through multiple molecular targets, the inhibition of the growth of oral cancer cell lines in vitro, the potency of curcumin against oral cancer in vivo, and the anticancer effect of curcumin in murine thymoma cells.

Hematologic Cancers

In vitro, curcumin has been shown to have synergistic and remedial properties in leukemia. Studies have also demonstrated curcumin’s therapeutic properties in vivo.

 Curcumin has been found to inhibit cellular proliferation and enhance apoptosis in various lymphoma cell lines in vitro. Also, numerous reports suggest that curcumin exhibits antiproliferative effects against multiple myeloma cells.

 The chemoprotective effects of curcumin on several carcinogen-induced skin cancer models have been investigated, reporting that curcumin reduced the number of tumors per mouse and decreased the number of tumor-bearing mice.

 Curcumin and its analogs have been found to have antitumor effects in bone cancer cells and in human malignant glioblastoma cells.

 In addition, curcumin has been shown to have potential activity against cancer symptoms, such as neuropathic pain, depression, fatigue, and neurodegeneration.

 The cited studies ― in vitro, in vivo, and human ― establish curcumin’s promise and reveal its therapeutic value, say the authors. “The safety, low cost, and already proven efficacy of this ‘age-old’ natural medicine makes it a promising agent for the treatment of an ‘old-age’ disease like cancer.”