Synergistic Potentiation Of Interferon Activity With Maitake Mushroom D-Fraction On Bladder Cancer Cells

Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology
Article Date: 01 Dec 2009 - 0:00 PDT

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UroToday.com - In this in vitro study, we demonstrated that growth inhibitory activity of interferon-α2b (IFN-α2b) on bladder cancer T24 cells was synergistically enhanced with maitake mushroom D-fraction (PDF), a bioactive extract. IFN-α2b at 20,000 (20K) IU/ml and PDF at 700 μg/ml have been shown to induce a 50% and 53% growth reduction, respectively. However, when these two agents were combined, the combination of 10K IU/ml IFN-α2b and 200 μg/ml PDF resulted in a nearly 75% reduction in cell growth. This finding suggests that the IFN-α2b/PDF-induced growth reduction appears to be due to the synergistic effect, because the given concentrations of neither agent by itself have any such growth inhibitory effects - i.e. no growth reduction attained with either IFN-α2b (10K IU/ml) or PDF (200 μg/ml) alone. In addition, separate study showed that compared to the amount of sole IFN-α2b (e.g. 50K IU/ml) needed to be effective, merely "1/5th" of that (i.e. 10K IU/ml) would be sufficient to demonstrate the better, enhanced growth inhibitory activity in combination with PDF (200 μg/ml). Thus, the relatively low and ineffective concentrations of IFN-α2b and PDF would be required for exhibiting the significant growth inhibitory activity on bladder cancer cells when they were combined.

Cell cycle analysis showed that a ~63% decrease in the S-phase cell number with a concomitant 55% increase in the G1-phase cell number following the treatment of IFN-α2b/PDF combination. This is indicative of a blockage of cells entering from the G1 to the S phase - i.e. a G1 cell cycle arrest. It is then plausible that growth inhibitory action of IFN-α2b/PDF combination may primarily target the G1-S phase progression in the cell cycle. In addition, this G1 growth arrest was further supported by the fact that double-stranded DNA-dependent protein kinase (DNA-PK), which plays an important role in the cell cycle regulation, was significantly activated by the IFN-α2b/PDF combination. Since IFNs have been shown to induce DNA fragmentation, generating small, low-molecular weight DNA, it is possible that DNA-PK would be likely activated with such small DNA fragments, which are known to serve as an activator required for its enzymatic activation. Taken together, these results suggest that the growth inhibitory mechanism of IFN-α2b/PDF combination might be associated with an accumulation of small DNA fragments, triggering DNA-PK activation that may then act primarily on the cell cycle to cease proliferation of bladder cancer cells.

The clinical relevance of this study is that the low-dose IFN-α2b/PDF combination may provide an alternative, improved intravesical immunotherapy for patients with superficial bladder cancer. IFN-α has been used as an intravesical agent for treating superficial bladder cancer, resulting in a ~40% response rate in patients, which was not yet good or satisfactory as expected. In addition, IFN-α therapy has several drawbacks, especially its high cost. A standard intravesical IFN-α instillation is carried out with 50-100 million IU of IFN-α, which needs to be repeatedly administered because of its short retention time inside the bladder. It is not only costly but also uncertain if such a repeated high-dose regimen would actually provide an effective antitumor immunity. To distinctly improve such an IFN-α immunity, combination therapy (e.g. IFN-α/BCG combination) has been postulated and conducted in pilot clinical trials and animal studies, showing the better and encouraging outcomes. Thus, our study also implies that the combination of IFN-α2b and PDF could be considered another potential intravesical therapy for superficial bladder cancer.

Although many urologists or physicians would use IFN-α2b in such combination therapy without much hesitation, they might be uncertain and reluctant to use PDF because they are not familiar with this mushroom extract. For a better understanding, additional information on PDF would be provided herein.

Maitake mushroom D-fraction (PDF) is a bioactive proteoglucan (i.e. β-glucan) extracted from maitake mushrooms (Grifola frondosa). It has been subjected to extensive scientific studies for nearly 30 years, revealing a number of its medicinal properties that could provide remarkable health benefits. Particularly, a number of published and unpublished studies have shown two major biological activities of PDF, immunomodulatory and antitumor activities, implying its clinical and therapeutic utilities. Its other potential physiological benefits include treatment for diabetes, hypertension, hypercholesterolemia, viral infection, and obesity. Antiviral activity of PDF on human immunodeficiency virus (HIV)/AIDS was also confirmed by the U.S. National Cancer Institute (NCI). The standardized PDF has been commercially available for medical/scientific research or personal use. Antitumor or anticancer effects of PDF have been demonstrated in a variety of cancers (including bladder cancer) in vitro and in vivo (animals). Although not many human trials have been performed using PDF, it would be worthwhile mentioning a non-randomized clinical study of PDF on 165 patients with various types of advanced cancers. This study showed tumor regression or significant symptomatic improvements with PDF in 73% of breast cancer patients, 67% of lung cancer patients, and 47% of liver cancer patients. When PDF was given to the patients receiving chemotherapy, the response rates have significantly improved and its various side effects on all cancer patients were also ameliorated with PDF administration. It is believed that PDF might help maintain optimal activities of key immune-competent cells to minimize such side effects caused by chemotherapy that often lowers or damages the immune function. In fact, several adverse symptoms such as nausea, hair loss and leukopenia have been alleviated in 90% of those patients, while a reduction in pain was reported in 83% of patients. Thus, PDF may also help improve quality of life in patients and would be considered a useful adjuvant in ongoing cancer chemotherapy.

Moreover, the safety of PDF was further supported by the fact that the US Food and Drug Administration (FDA) had exempted a phase I study of toxicology tests. Additionally, the FDA has approved PDF for the Investigational New Drug (IND) application for a phase II pilot study on patients with advanced breast and prostate cancer.

After all, this information on PDF would provide sufficient and compelling support for its potential use in combination therapy (with IFN-α2b) for bladder cancer patients.

In summary, our study shows that the combination of IFN-α2b and PDF synergistically potentiates the growth inhibitory activity on bladder cancer cells. In fact, to achieve the similar efficacy induced with the given concentration of IFN-α2b alone, only 1/5th of that concentration was required in this combination. It is thus plausible that PDF may not only help potentiate IFN-α2b activity but also help reduce the cost of treatment. However, further studies are yet required to establish how these effective concentrations of IFN-α2b and PDF in vitro would be actually extrapolated in animals or humans (i.e. physiological concentrations). Such studies are indeed warranted.

Written by Brandon Louie, Srinivas Rajamahanty, John Won, Muhammad Choudhury and Sensuke Konno as part of Beyond the Abstract on UroToday.com.

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