Dr. Polans is Associate Professor of Ophthalmology and Visual Sciences and Associate Professor of Biomolecular Chemistry at the University of Wisconsin-Madison. He is an expert in the biochemistry and molecular biology of the eye. His research program encompasses diverse fields of investigation including ocular tumors (especially melanoma), the remote effects of cancer in the eye as well as fundamental issues related to phototransduction.
Pilot Study of a "Large-Eye," Surgically Induced Dry Eye Rabbit Model by Selective Removal of the Harderian, Lacrimal, and Meibomian Glands.
Ocul Oncol Pathol. 2017 Dec;4(1):52-56
Authors: Polans AS, McAnulty JF, Phelps PO, Darjatmoko SR, Burris CK, Albert DM
Background/Aims: Establish a reliable rabbit dry eye (DE) model.
Methods: An interventional cohort study surgically removing glands contributing to the tear film. Eight rabbits were studied after removal of left lacrimal, Harderian, or both glands. Additional rabbits had Meibomian glands in the left eye thermally obstructed. All were followed for 10 weeks with phenol red thread (PRT) and slit-lamp examination with 2% fluorescein. We assessed corneal sensitivity using a Cochet-Bonnet esthesiometer. Outcome measures were severity/duration of reduced PRT, punctate epithelial erosions (PEE), and histologic evidence of corneal pannus.
Results: Fluorescein staining demonstrated signs of dryness including PEE in all of the interventional eyes. The subjective measurement of epithelial erosions correlated with decreased tear production. PRT measurements in the control eyes averaged 31.54 mm (±1.83) and 22.71 mm (±1.60) in the eight left eyes, without loss of corneal sensitivity.
Conclusions: Surgical removal of either the Harderian or lacrimal gland results in statistically significant decreases in tear volume and the development of severe DE. Removal of both glands results in the occurrence of a DE of comparable severity/duration to removal of either the lacrimal or Harderian gland alone. Meibomian gland obstruction contributes less to the DE model.
PMID: 29344500 [PubMed]
A synergetic screening approach with companion effector for combination therapy: application to retinoblastoma.
PLoS One. 2013;8(3):e59156
Authors: Mahida JP, Antczak C, Decarlo D, Champ KG, Francis JH, Marr B, Polans AS, Albert DM, Abramson DH, Djaballah H
For many cancers, the lack of potency and the toxicity of current drugs limits the dose achievable in patients and the efficacy of treatment. Among them, retinoblastoma is a rare cancer of the eye for which better chemotherapeutic options are needed. Combination therapy is a compelling approach to enhance the efficacy of current treatment, however clinical trials to test rationally designed combinations of approved drugs are slow and expensive, and limited by our lack of in-depth knowledge of drug specificity. Since many patients already turn to nutraceuticals in hopes of improving their condition, we hypothesized that certain approved drugs could potentially synergize with widely consumed supplements. Following this hypothesis, we devised an alternative screening strategy aimed at taking advantage of a bait compound such as a nutraceutical with potential therapeutic benefits but low potency, by screening chemical libraries for approved drugs that synergize with this companion effector. As a proof of concept, we sought to identify approved drugs with synergetic therapeutic effects toward retinoblastoma cells in combination with the antioxidant resveratrol, popular as a supplement. We systematically tested FDA-approved drugs and known bioactives seeking to identify such pairs, which led to uncovering only a few additive combinations; but to our surprise, we identified a class of anticancer drugs widely used in the clinic whose therapeutic effect is antagonized with resveratrol. Our observations could explain in part why some patients do not respond well to treatment. Our results validate this alternative approach, and we expect that our companion effector strategy could significantly impact both drug discovery and the nutraceutical industry.
PMID: 23527118 [PubMed - indexed for MEDLINE]
Anti-tumor and immunomodulatory activity of resveratrol in vitro and its potential for combining with cancer immunotherapy.
Int Immunopharmacol. 2011 Nov;11(11):1877-86
Authors: Soto BL, Hank JA, Darjatmoko SR, Polans AS, Yanke EM, Rakhmilevich AL, Seo S, Kim K, Reisfeld RA, Gillies SD, Sondel PM
We evaluated the anti-tumor effect of Resveratrol (RV) on M21 and NXS2 tumor cell lines and its immunosuppressive activity on human and murine immune cells to determine the potential for combining RV and immunotherapy. In vitro, concentrations of RV≥25 mcM, inhibited cell proliferation, blocked DNA synthesis and induced G1 phase arrest in tumor and immune cells. RV at 12-50 mcM inhibited antibody dependent cell mediated cytotoxicity (ADCC) of tumor cells facilitated by the hu14.18-IL2 immunocytokine (IC). The in vivo anti-tumor and immunomodulating activity of RV given systemically were assessed in mice. Results showed that this RV regimen inhibited the growth of NXS2 tumors in vivo but did not appear to interfere with blood cell count, splenocyte or macrophage function. Thus, RV may be a candidate for combining with immunotherapy.
PMID: 21854876 [PubMed - indexed for MEDLINE]
Resveratrol modulates the malignant properties of cutaneous melanoma through changes in the activation and attenuation of the antiapoptotic protooncogenic protein Akt/PKB.
Melanoma Res. 2011 Jun;21(3):180-7
Authors: Bhattacharya S, Darjatmoko SR, Polans AS
Resveratrol, a nontoxic natural product, exhibits multifaceted biological effects including antimutagenic and anticancer properties. We examined the effect of resveratrol on the expression and activation of Akt/protein kinase B and its impact on melanoma cell migration and invasiveness. We also explored the use of resveratrol as an antimalignant treatment option against skin melanoma in mouse models of the disease. Akt expression and activity were determined by a combination of real-time PCR and western blot analysis. Cell lines stably expressing Akt or a dominant negative variant were used to further establish the role of Akt during the response to resveratrol. Wound healing and transwell assays were used as in-vitro correlates of melanoma cell migration and invasiveness. The efficacy of resveratrol in the treatment of melanoma was assessed in two syngeneic mouse models. Resveratrol downregulated and inactivated Akt in B16F10 and B16BL6 melanoma cells. Resveratrol also inhibited the migratory and invasive properties of these highly malignant cells. The reduction of cell migration and invasion, however, was reversed in cell lines overexpressing Akt or after cotreatment with pharmacological inhibitors that blocked Akt degradation. Dominant-negative Akt cells were more sensitive to resveratrol and had diminished migratory properties. Oral treatment with resveratrol reduced primary tumor volume, Akt expression, and the propensity for metastasis in syngeneic mouse models of melanoma. These results suggest that resveratrol can reduce the malignant properties of highly invasive melanoma cells by inactivating Akt. The nontoxic targeting of Akt by resveratrol makes it an attractive treatment option for melanoma.
PMID: 21407133 [PubMed - indexed for MEDLINE]
The anti-tumor effect of resveratrol alone or in combination with immunotherapy in a neuroblastoma model.
Cancer Immunol Immunother. 2011 May;60(5):731-8
Authors: Soto BL, Hank JA, Van De Voort TJ, Subramanian L, Polans AS, Rakhmilevich AL, Yang RK, Seo S, Kim K, Reisfeld RA, Gillies SD, Sondel PM
We investigated the anti-tumor effect of peritumoral resveratrol in combination with immunotherapy in vivo in neuroblastoma-bearing mice. Subcutaneous NXS2 tumors were induced in A/J mice. On day 10, some mice received 15 mcg of intravenous immunocytokine for 5 days, mice received 20 mg of peritumoral resveratrol twice a week (starting on day 12) for a total of 5 injections, and a separate group received a combination of both regimens. Tumor progression and survival were assessed every 3-4 days. Blood and primary tumor tissue samples were collected on day 20 for Complete Blood Count and CD45 immunohistochemistry and histology, respectively. The primary tumor regressed in all mice receiving peritumoral resveratrol. Most of these mice receiving peritumoral resveratrol alone developed metastatic tumors and recurrence of the primary tumor after cessation of therapy. When resveratrol and immunocytokine regimens were combined, 61% of the mice receiving this combination therapy resolved their primary tumors and survived without developing metastatic tumors, compared to 15 and 13% receiving resveratrol or immunocytokine alone, respectively. None of the therapeutic regimes prevented lymphocyte infiltration or affected the complete blood count. Greater necrosis was observed microscopically in tumors from mice receiving the combination therapy. These results demonstrate that the combination therapy of peritumoral resveratrol plus intravenous immunocytokine provides better anti-tumor effects in this model than either therapy alone.
PMID: 21340652 [PubMed - indexed for MEDLINE]
Resveratrol: challenges in translation to the clinic--a critical discussion.
Clin Cancer Res. 2010 Dec 15;16(24):5942-8
Authors: Subramanian L, Youssef S, Bhattacharya S, Kenealey J, Polans AS, van Ginkel PR
Low cancer survival rates and the serious side effects often associated with current chemotherapeutics highlight the need for new and effective nontoxic anticancer agents. Since 1997 when Jang and colleagues first described resveratrol's ability to inhibit carcinogenesis, it has consistently proven effective at tumor inhibition in diverse human cancer models. This finding has raised the hope that resveratrol would pioneer a novel class of nontoxic chemotherapeutics. As a consequence of initial basic and preclinical studies, resveratrol is now being extensively promoted in the unregulated nutraceutical sector. However, some fundamental aspects of resveratrol's action need to be understood before it can be developed into a clinically viable anticancer drug. These areas pertain to the key mechanism(s) by which resveratrol potentiates its antitumor effects. Current research suggests that these mechanisms might be through novel pathways, requiring an understanding of cellular uptake, sentinel targets, and in vivo biological networks. The metabolism of resveratrol and its bioavailability also warrant further consideration in light of recent in vitro and in vivo studies. Finally, we need to appreciate the sorts of information about resveratrol that may translate between different disease entities. We present a critical discussion of these issues and suggest important experiments that could pave the way to the successful translation of resveratrol to the clinic.
PMID: 21045084 [PubMed - indexed for MEDLINE]