Narrow Results

Tumor metastasis is a major cause of mortality in cancer patients. The anti-metastatic effect of tetrandrine, an alkaloid isolated from Stephania tetrandrae S. Moore, was investigated in a pulmonary metastatic model of colorectal cancer-bearing mice. Tetrandrine decreased the viability of murine colorectal adenocarcinoma CT26 cells in a time- and dose-dependent manner. CT26 cells were injected into BALB/c mice via a tail vein to establish pulmonary metastases. After this, the mice were given intraperitoneal injections of tetrandrine (10 mg/kg/day), 5-fluorouracil (5-FU) at the same dose, or vehicle for 5 consecutive days. Mice treated with tetrandrine had 40.3% fewer metastases than vehicle-treated mice, and those treated with 5-FU had 36.9% fewer metastases than controls. Both tetrandrine- and 5-FU-treated mice survived longer than mice in the untreated control group. There was no acute toxicity or obvious changes in body weight in any of the mice. These results suggest that tetrandrine may be a useful anti-metastatic agent.

In the United States, many patients, including cancer patients, concurrently take prescription drugs and herbal supplements. Co-administration of prescription medicines and herbal supplements may have negative outcomes via pharmacodynamic and pharmacokinetic herb-drug interactions. However, multiple constituents in botanicals may also yield beneficial pharmacological activities. Botanicals could possess effective anticancer compounds that may be used as adjuvants to existing chemotherapy to improve efficacy and/or reduce drug-induced toxicity. Herbal medicines, such as ginseng, potentiated the effects of chemotherapeutic agents via synergistic activities, supported by cell cycle evaluations, apoptotic observations, and computer-based docking analysis. Since botanicals are nearly always administrated orally, the role of intestinal microbiota in metabolizing ginseng constituents is presented. Controlled clinical studies are warranted to verify the clinical utility of the botanicals in cancer chemoprevention.

Natural products play an important role in cancer therapeutics, and lately more attentions have been paid to the prevention of major lethal malignancies, such as colorectal cancer (CRC). After oral ingestion, botanicals' parent compounds can be converted to their metabolites by the enteric microbiome, and these metabolites may have different bioactivities and variable bioavailability. In this study, we used an active ginseng metabolite, protopanaxadiol (PPD), as an example to assess its colon cancer preventive effect by comparing its effect with the treatment effect of fluorouracil (5-FU). A xenograft tumor nude mouse model with human colon cancer cell inoculation was used. After preventive PPD or treatment 5-FU administration with the same dose (30 mg/kg), tumor growth inhibition was evaluated by both a Xenogen bioluminescence imaging technique and manual tumor size measurement. Our data showed that preventive PPD very significantly inhibited the tumor growth compared to 5-FU (p < 0.01). Our data suggest that the PPD is a promising cancer prevention agent. More studies are needed to explore the chemopreventive actions of PPD and its potential clinical utility.

Combining innocuous natural products with cytotoxic agents may enhance the effectiveness of chemotherapy. Tangeretin is a citrus flavonoid that has antineoplastic properties, but its mechanism of action is still unknown. Here, we used a high throughput-screening (HTS) platform to screen for drugs that may synergize with tangeretin and confirmed the top hits against colorectal cancer (CRC) cells in vitro and in vivo. 5-Fluorouracil (5-FU) and PI3K/Akt inhibitors have come out as top hits that show a strong synergy effect with tangeretin by HTS. We further confirmed the synergistic effect of tangeretin with 5-FU against CRC cells in vitro and in vivo. Since 5-FU can increase microRNA-21 (miR-21) expression and activate PI3K/Akt signaling, we addressed if tangeretin acted at this level. In 5-FU treated cells, tangeretin inhibited miR-21 induction, rescued the expression of the target PTEN, reduced Akt activation, and induced autophagy. Together, our data indicated that a natural product, such as tangeretin, can modulate miR-21 expression and that this pathway might be a potential therapeutic target for CRC. Combining tangeretin with 5-FU may be useful in the clinic, since 5-FU is the current first line drug for treating CRC.

The poor prognosis for patients with metastatic cancer and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Dosage of systemically administered chemotherapeutic agents is limited by the toxicity to normal tissues, often precluding achievement of therapeutic indices of sufficient levels to affect complete cures. Malignant brain tumors pose further limitations to available therapies due to the infiltrative nature of the tumor cells throughout the brain and the presence of the blood–brain barrier. Novel anti-cancer treatment approaches must be more tumor-localized and tumor cell-selective to improve effectiveness and clinical outcome.

Neural stem (and/or progenitor) cells (NSCs) display inherent tumor-tropic properties that can be exploited for targeted delivery of anti-cancer agents to invasive and metastatic tumors. We and others have previously demonstrated that NSCs can deliver bioactive therapeutic agents to elicit a significant anti-tumor response in animal models of intracranial glioma, medulloblastoma and melanoma brain metastases. Recent studies demonstrate retention of tumor-tropic properties when NSCs are injected into the peripheral vasculature, localizing to multiple tumor sites in animal models of disseminated neuroblastoma and orthotopic breast carcinoma, with little accumulation in normal tissues. We postulate that this NSC-mediated, tumor-selective approach can maximize local concentrations of anti-cancer agents to tumor foci, while minimizing toxicity to normal tissues. This would potentially achieve therapeutic indices sufficient to eradicate invasive tumors that are otherwise lethal.

Several well-characterized immortalized murine and human NSC lines have been extensively studied for the determination of their therapeutic potential in animal tumor models of glioblastoma, melanoma brain metastases, medulloblastoma, and disseminated neuroblastoma. In all invasive and metastatic solid tumor models, 70–90% therapeutic efficacy was achieved as measured by increased long-term survival or decreased tumor burden. Other studies in the literature demonstrated the achievement of similar results with nonimmortalized NSC pools modified with various therapeutic genes, further verifying the NSC tumor tropism phenomenon. However, these pools are more difficult to keep consistent over time and passage, adding more variability to pre-clinical trials and more difficulty in creating uniform master cell banks for clinical trials.

We suggest that using a stable, sustainable and easily expandable clonal NSC line will circumvent the problems associated with characterization, senescence, and replenishment sources of primary stem cell pools. It would also allow for cost-effective and accessible patient trials. At the very least, such NSC lines can serve in proof-of-concept pre-clinical studies, where tumor types and therapeutic regimens are being tested. Preliminary biodistribution studies indicate that one such immortalized human NSC line (HB1.F3) is safe, non-immunogenic and non-tumorigenic. Furthermore, these cells retain their tumor-tropic property when modified to express therapeutic transgenes. Genomic stability and retention of tumor-tropic properties over time and passage has also been confirmed, making it a very promising line for clinical trials.

Regardless of which NSCs move towards therapeutic cancer trials, safety and feasibility would be best assessed first in patients with no alternative treatments, such as recurrent high-grade gliomas. These aggressive tumor cells infiltrate normal brain, and are not readily treatable by resection, irradiation, chemotherapy or gene therapy. In rodent models of orthotopic human brain tumors, it has been demonstrated that HB1.F3 NSCs can selectively target invasive tumor cells and distant micro tumor foci, achieving therapeutic efficacy with an enzyme/prodrug strategy. This serves as one example of many different anti-cancer agents that could be similarly delivered to tumor sites throughout the body.