BioCis Pharma Ltd

Turku, Finland

BioCis Pharma Ltd

Turku, Finland

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Arentsen H.C.,Radboud University Nijmegen | Jansen C.F.J.,Radboud University Nijmegen | Hulsbergen-Van De Kaa C.A.,Radboud University Nijmegen | Laihia J.K.,BioCis Pharma Ltd. | And 5 more authors.
Journal of Urology | Year: 2012

Purpose: We determined the effect of protodynamic therapy against bladder cancer cells in vitro and in vivo. We investigated cis-urocanic acid in rat bladder cancer cell cultures and in an orthotopic rat urothelial carcinoma model to assess its safety and antiproliferative activity. Materials and Methods: The rat bladder cancer cell line AY-27 was exposed to cis-urocanic acid (BioCis Pharma, Turku, Finland) at pH 6.5 or 7.4 for 2 hours. Cell viability was measured by colorimetric assay at 24 and 48 hours. For in vivo experiments AY-27 cells were instilled into the acid treated bladder of 17 rats. After 4, 7 and 10 days 14 rats were treated intravesically with cis-urocanic acid 6% (weight per volume) or vehicle. Rats were sacrificed on day 12 and the bladders were dissected. Immunohistochemical staining was done to assess apoptosis (caspase-3) and cell proliferation (Ki-67) in vivo. Results: Cis-urocanic acid caused dose dependent, pH dependent inhibition of AY-27 cell proliferation, showing the protodynamic action at concentrations of 0.5% and 1%. At higher cis-urocanic acid doses complete cell death was observed. All tumors detected in animals treated with vehicle were muscle invasive (stage T2 or greater) but only 43% of tumors were muscle invasive in the cis-urocanic acid treated group (p = 0.049). There was no difference in the percent of apoptotic or proliferating tumor cells between treatment groups. No signs of toxicity were observed. Conclusions: Cis-urocanic acid showed direct antiproliferative activity against rat bladder cancer cells in vitro and antitumor effects in vivo. It may have therapeutic potential as an intravesical agent for nonmuscle invasive bladder cancer. © 2012 American Urological Association Education and Research, Inc.


Koulu L.M.,University of Turku | Laihia J.K.,University of Turku | Laihia J.K.,BioCis Pharma Ltd | Peltoniemi H.-H.,University of Turku | Jansen C.T.,University of Turku
Journal of Investigative Dermatology | Year: 2010

Polymorphic light eruption (PLE) is a common skin disorder provoked by exposure to UVR. Its clinical symptoms resemble those of a contact allergic reaction. PLE is generally considered a T-cell-mediated autoimmune reaction toward a yet unidentified antigen formed in UVR-exposed skin. Predisposition to such an immune reaction may result from aberrant epitope formation, increased immune reactivity to a universal epitope, or diminished propensity to UVR-induced immunosuppression or to the induction of tolerance. In a study comprising a total of 24 PLE patients and 24 healthy sex- and age-matched controls, we found that both groups demonstrated similar immunosuppression of contact sensitization to diphenylcyclopropenone by earlier exposure to solar-simulating UVR. However, only 1 out of 13 PLE patients (8%) versus 6 out of 11 controls (55%) that had been immunosuppressed by UVR exhibited a state of immunotolerance toward the same allergen after 10-24 months (P=0.023). We conclude that the impaired propensity to UVR-induced allergen-specific immunotolerance may promote recurrent PLE. © 2010 The Society for Investigative Dermatology.


Konkol Y.,Pharmatest Services | Konkol Y.,University of Turku | Bernoulli J.,Pharmatest Services | Streng T.,University of Turku | And 3 more authors.
Neurourology and Urodynamics | Year: 2016

Aims: The aim was to study the effect of intravesically instilled cis-urocanic acid (cis-UCA) on bladder function in an experimental rat model of acute bladder inflammation. Hyaluronic acid (HA) was used as a comparator compound. Methods: Bladder irritation was induced in female rats by intravesical hydrochloric acid (HCl) infusion. Vehicle, 0.5% HA, or 2% cis-UCA solutions were infused intravesically twice a day for three consequent days. On the fourth day, urodynamical measurements were performed, the animals were sacrificed, and the bladders were removed for histopathological assessment. Results: HCl treatment caused significant impairment of bladder function indicated by decreased micturition intervals and voided urine volumes and induced severe voiding dysfunction observed as occurrence of overflow incontinence. These functional changes were accompanied by increased bladder weight, hemorrhage, and infiltration of inflammatory cells into the urothelium. Intravesical cis-UCA treatment recovered bladder function by significantly prolonging the micturition interval, increasing the voided volume, and reducing the occurrence of overflow incontinence. All these changes were comparable to the effects of HA. Conclusions: Intravesical administration of cis-UCA was able to partially recover bladder function impaired by chemical irritation. Cis-UCA may offer a novel intravesical treatment option in some inflammatory conditions of the bladder. Neurourol. Urodynam. 35:786–791, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.


Laihia J.K.,BioCis Pharma Ltd. | Kallio J.P.,University of Turku | Taimen P.,University of Turku | Kujari H.,University of Turku | And 2 more authors.
Journal of Investigative Dermatology | Year: 2010

The extracellular tumor microenvironment is acidified, whereas the intracellular pH of tumor and stromal cells is neutral. cis-Urocanic acid (cis-UCA), an endogenous compound of the skin, can acidify the cytosol by transporting protons into the cells. This phenomenon, termed the protodynamic concept, was studied here in human cancer cells. cis-UCA dose-dependently reduced the number of viable human melanoma, cervical carcinoma, and fibrosarcoma cells at weakly acidic extracellular pH. The intracellular pH decreased by up to 0.5 pH units in a concentration-dependent manner with 0.3-30 m cis-UCA at extracellular pH 6.5 but not at pH 7.4. Under the same conditions, 30 mM cis-UCA induced annexin-V binding and activation of caspase-3 in A2058 melanoma cells as signs of apoptotic cell death. Finally, growth of human melanoma xenografts in SCID mice was suppressed by 60% following intratumoral injection of cis-UCA. Accordingly, the percentage of tumor necrosis and active caspase-3-immunopositive cells increased, whereas proliferation activity decreased. These results identify cis-UCA as an anticancer agent inhibiting melanoma growth by immediate intracellular acidification followed by apoptotic cell death in vivo. © 2010 The Society for Investigative Dermatology.


Laihia J.K.,BioCis Pharma Ltd | Taimen P.,University of Turku | Kujari H.,University of Turku | Leino L.,BioCis Pharma Ltd
British Journal of Dermatology | Year: 2012

Background cis-Urocanic acid (cis-UCA) is an endogenous immunosuppressive molecule of the epidermis. Objectives We investigated the effects of topical cis-UCA creams (2·5% and 5%) in acute and subacute mouse models of skin inflammation. Methods Acute skin irritation was induced by applying dimethyl sulphoxide (DMSO) on the earlobe of CD-1 mice. Topical cis-UCA, hydrocortisone (1%) or tacrolimus (0·1%) were applied 10 min later. In another model, subacute inflammation was provoked and maintained by three applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the ears of NMRI mice on days 1, 2 and 4. The test products were applied topically twice a day during 6 days. Results In the acute DMSO model, cis-UCA creams suppressed ear swelling at 1 h significantly more efficiently than hydrocortisone (P < 0·01) and tacrolimus (P < 0·001). Ear swelling was significantly inhibited by cis-UCA (P < 0·001) in the subacute TPA model as well. The 5% cream also decreased erythema, whereas tacrolimus enhanced skin reddening. Treatments with cis-UCA did not affect TPA-induced infiltration of neutrophils to the skin. In contrast to hydrocortisone, cis-UCA did not reduce epidermal thickness. Conclusions The results suggest that cis-UCA - unlike hydrocortisone and tacrolimus - is efficient in both acute and subacute skin inflammation, attenuating skin oedema and erythema. Topical drug therapy with cis-UCA may provide a safe and effective drug treatment modality in inflammatory skin disorders. © 2012 British Association of Dermatologists.


Pelttonen J.M.,Clinical Research Services Turku | Pelttonen J.M.,University of Turku | Pylkkanen L.,BioCis Pharma Ltd | Jansen C.T.,University of Turku | And 4 more authors.
Acta Dermato-Venereologica | Year: 2014

New treatment modalities are needed in atopic dermatitis. We evaluated the pharmacokinetics, safety, tolerability, and efficacy of topical cis-urocanic acid (cis-UCA) cream in randomised vehicle-controlled double-blinded clinical trials. The subjects received 5% cis-UCA emulsion cream and control vehicle on volar forearms after right-left randomisation. Study 1: 16 healthy subjects received one dose on the skin and, a week later, on DMSO- irritated skin. Study 2: 16 healthy subjects received 2 daily doses for 10 days. Study 3: 13 patients with mild to moderate disease were treated on selected skin lesions twice daily for 28 days. Study treatments were well tolerated. cis-UCA remained close to endogenous levels in plasma and urine. cis-UCA reduced transepidermal water loss (TEWL) both in healthy subjects and in the patients. Eczema area severity index and physician's global assessment improved from baseline with both treatments. cis-UCA cream improved skin barrier function and suppressed inflammation in the human skin. © 2014 The Authors.


Peuhu E.,Åbo Akademi University | Kaunisto A.,Åbo Akademi University | Laihia J.K.,BioCis Pharma Ltd. | Leino L.,BioCis Pharma Ltd. | Eriksson J.E.,Åbo Akademi University
BMC Cancer | Year: 2010

Background: cis-urocanic acid (cis-UCA) is an endogenous amino acid metabolite capable of transporting protons from the mildly acidic extracellular medium into the cell cytosol. The resulting intracellular acidification suppresses many cellular activities. The current study was aimed at characterizing the molecular mechanisms underlying cis-UCA-mediated cytotoxicity in cultured cancer cells.Methods: 5367 bladder carcinoma cells were left untreated or treated with cis-UCA. Cell death was assessed by measuring caspase-3 activity, mitochondrial membrane polarization, formation and release of cytoplasmic histone-associated DNA fragments, and cellular permeabilization. Cell viability and metabolic activity were monitored by colorimetric assays. Nuclear labelling was used to quantify the effects of cis-UCA on cell cycle. The activity of the ERK and JNK signalling pathways was studied by immunoblotting with specific antibodies. Phosphatase activity in cis-UCA-treated cells was determined by assay kits measuring absorbance resulting from the dephosphorylation of an artificial substrate. All statistical analyses were performed using the two-way Student's t-test (p < 0.05).Results: Here we report that treatment of the 5637 human bladder carcinoma cells with 2% cis-UCA induces both apoptotic and necrotic cell death. In addition, metabolic activity of the 5637 cells is rapidly impaired, and the cells arrest in cell cycle in response to cis-UCA. Importantly, we show that cis-UCA promotes the ERK and JNK signalling pathways by efficiently inhibiting the activity of serine/threonine and tyrosine phosphatases.Conclusions: Our studies elucidate how cis-UCA modulates several cellular processes, thereby inhibiting the proliferation and survival of bladder carcinoma cells. These anti-cancer effects make cis-UCA a potential candidate for the treatment of non-muscle invasive bladder carcinoma. © 2010 Peuhu et al; licensee BioMed Central Ltd.


Jauhonen H.-M.,Kuopio University Hospital | Kauppinen A.,University of Eastern Finland | Paimela T.,University of Eastern Finland | Laihia J.K.,BioCis Pharma Ltd | And 5 more authors.
Molecular Vision | Year: 2011

Purpose: The cornea is sensitive to ultraviolet B (UV-B) radiation-induced oxidative stress and inflammation. Its clinical manifestations are photokeratitis and climatic droplet keratopathy. Urocanic acid (UCA) is a major endogenous UVabsorbing chromophore in the epidermis and it is also an efficacious immunosuppressant. We have previously shown that cis-UCA can suppress UV-B-induced interleukin-6 and -8 secretion and cytotoxicity in human corneal epithelium (HCE) cells. In the current study, we further wanted to investigate the effects of cis-UCA on UV-B-induced inflammatory and apoptotic responses in HCE-2 cells, focusing on the nuclear factor kappa B (NF-κB) and AP-1 (subunits c-Fos and c-Jun) signaling pathways. Methods: After exposing HCE-2 cells to UV-B and cis-UCA, DNA binding of c-Fos, c-Jun and NF-κB was measured with ELISA. In addition, the endogenous levels of phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase (phospho-SAPK/JNK) and phospho-c-Jun were determined. The proliferative capacity of HCE-2 cells was also quantified, and the cytotoxicity of the cis-UCA and UV-B treatments was monitored by measuring the release of lactate dehydrogenase enzyme in the culture medium. Results: UV-B irradiation induced the binding of transcription factors c-Jun, c-Fos, and NF-κB to DNA. Cis-UCA inhibited the binding of c-Jun and c-Fos but not that of NF-κB. Moreover, UV-B increased the levels of phospho-c-Jun and phospho-JNK, and the expression of both was attenuated by cis-UCA. Cis-UCA also alleviated the UV-B-induced apoptosis and proliferative decline in human corneal cells. Conclusions: The results from this study suggest that cis-UCA suppresses JNK signaling pathway, which provides potential for treating UV-B-induced inflammatory defects in human corneal cells. © 2011 Molecular Vision.


PubMed | BioCis Pharma Ltd
Type: Journal Article | Journal: The British journal of dermatology | Year: 2012

cis-Urocanic acid (cis-UCA) is an endogenous immunosuppressive molecule of the epidermis.We investigated the effects of topical cis-UCA creams (25% and 5%) in acute and subacute mouse models of skin inflammation.Acute skin irritation was induced by applying dimethyl sulphoxide (DMSO) on the earlobe of CD-1 mice. Topical cis-UCA, hydrocortisone (1%) or tacrolimus (01%) were applied 10 min later. In another model, subacute inflammation was provoked and maintained by three applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the ears of NMRI mice on days 1, 2 and 4. The test products were applied topically twice a day during 6 days.In the acute DMSO model, cis-UCA creams suppressed ear swelling at 1 h significantly more efficiently than hydrocortisone (P < 001) and tacrolimus (P < 0001). Ear swelling was significantly inhibited by cis-UCA (P < 0001) in the subacute TPA model as well. The 5% cream also decreased erythema, whereas tacrolimus enhanced skin reddening. Treatments with cis-UCA did not affect TPA-induced infiltration of neutrophils to the skin. In contrast to hydrocortisone, cis-UCA did not reduce epidermal thickness.The results suggest that cis-UCA - unlike hydrocortisone and tacrolimus - is efficient in both acute and subacute skin inflammation, attenuating skin oedema and erythema. Topical drug therapy with cis-UCA may provide a safe and effective drug treatment modality in inflammatory skin disorders.


PubMed | BioCis Pharma Ltd
Type: Journal Article | Journal: The Journal of investigative dermatology | Year: 2010

The extracellular tumor microenvironment is acidified, whereas the intracellular pH of tumor and stromal cells is neutral. cis-Urocanic acid (cis-UCA), an endogenous compound of the skin, can acidify the cytosol by transporting protons into the cells. This phenomenon, termed the protodynamic concept, was studied here in human cancer cells. cis-UCA dose-dependently reduced the number of viable human melanoma, cervical carcinoma, and fibrosarcoma cells at weakly acidic extracellular pH. The intracellular pH decreased by up to 0.5 pH units in a concentration-dependent manner with 0.3-30 m cis-UCA at extracellular pH 6.5 but not at pH 7.4. Under the same conditions, 30 mM cis-UCA induced annexin-V binding and activation of caspase-3 in A2058 melanoma cells as signs of apoptotic cell death. Finally, growth of human melanoma xenografts in SCID mice was suppressed by 60% following intratumoral injection of cis-UCA. Accordingly, the percentage of tumor necrosis and active caspase-3-immunopositive cells increased, whereas proliferation activity decreased. These results identify cis-UCA as an anticancer agent inhibiting melanoma growth by immediate intracellular acidification followed by apoptotic cell death in vivo.

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