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Published in: Pathology & Oncology Research 4/2016

01-10-2016 | Original Article

Diindolylmethane and Lupeol Modulates Apoptosis and Cell Proliferation in N-Butyl-N-(4-Hydroxybutyl) Nitrosamine Initiated and Dimethylarsinic Acid Promoted rat Bladder Carcinogenesis

Authors: Bhoopathy Prabhu, Annamalai Sivakumar, Sivapatham Sundaresan

Published in: Pathology & Oncology Research | Issue 4/2016

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Abstract

Bladder cancer has been shown to resist programmed cell death with altered expression of both pro-apoptotic and anti-apoptotic proteins. To study is to investigate the apoptotic properties of Diindolylmethane (DIM) and Lupeol on N-Butyl-N-(4-hydroxybutyl) Nitrosamine (BBN) initiated and Dimethylarsinic Acid (DMA) promoted urinary bladder cancer. Sixty male Wistar rats were divided into 6 groups. Group I: Control. Group II: Rats were experimentally developed bladder carcinogenesis with BBN and DMA. Group III and IV: DIM and lupeol were administered after BBN treatment for 28 weeks. Group V and VI: DIM and lupeol alone treatment for 36 weeks. All the experimental rats were maintained and euthanized after 36 weeks protocol. Urinary bladder tissues were collected and processed for further investigations. Apoptotis and cell proliferative marker such as Bax, Bcl-2, caspase-3, caspase-9 and PCNA were quantified using immunohistochemical analysis. The Immunohistochemical expression of Bax, Bcl-2, caspase-3, caspase-9 and PCNA were aberrant in BBN + DMA treated tumor group. Administration of DIM and lupeol inhibited the progression of bladder cancer, induced the expression of apoptotic Bax, caspase-3, caspase-9 and inhibited the expression of anti-apoptotic Bcl-2, PCNA in the urinary bladder of rats. Administration of diindolylmethane and lupeol treatment induces apoptosis and cellular proliferation by its anti-carcinogenic properties. From our results DIM and lupeol would be the agent or adjunct for the treatment of bladder carcinogenesis.
Literature
1.
go back to reference Chavan S, Bray F, Lortet-Tieulent J, Jemal A (2014) International variations in bladder cancer incidence and mortality. Eur Urol 66:59–73CrossRefPubMed Chavan S, Bray F, Lortet-Tieulent J, Jemal A (2014) International variations in bladder cancer incidence and mortality. Eur Urol 66:59–73CrossRefPubMed
2.
go back to reference Botteman MF, Pashos CL, Redaelli A (2015) The health economics of bladder cancer: a comprehensive review of the published literature. Pharm Economics 21:1315–30CrossRef Botteman MF, Pashos CL, Redaelli A (2015) The health economics of bladder cancer: a comprehensive review of the published literature. Pharm Economics 21:1315–30CrossRef
3.
go back to reference Redondo-Gonzalez E, de Castro LN, Moreno-Sierra J (2015). Bladder Carcinoma Data with Clinical Risk Factors and Molecular Markers: A Cluster Analysis. Biomed. Res. Int. 168682. doi:10.1155/2015/168682. Redondo-Gonzalez E, de Castro LN, Moreno-Sierra J (2015). Bladder Carcinoma Data with Clinical Risk Factors and Molecular Markers: A Cluster Analysis. Biomed. Res. Int. 168682. doi:10.​1155/​2015/​168682.
5.
6.
go back to reference Kim B, Srivastava SK, Sun SH (2015) Caspase-9 as a therapeutic target for treating cancer. Expert Opin Ther Targets 19:11–127CrossRef Kim B, Srivastava SK, Sun SH (2015) Caspase-9 as a therapeutic target for treating cancer. Expert Opin Ther Targets 19:11–127CrossRef
7.
go back to reference Kirkin V, Joos S, Zornig M (2004) The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta 1644:229–249CrossRefPubMed Kirkin V, Joos S, Zornig M (2004) The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta 1644:229–249CrossRefPubMed
8.
go back to reference Sylvester RJ, Van der Meijden AP, Oosterlinck W (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49:466–77CrossRefPubMed Sylvester RJ, Van der Meijden AP, Oosterlinck W (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49:466–77CrossRefPubMed
9.
go back to reference Leonardi E, Girlando S, Serio G (1992) PCNA and Ki67 expression in breast carcinoma: correlations with clinical and biological variables. J Clin Pathol 45:416–419CrossRefPubMedPubMedCentral Leonardi E, Girlando S, Serio G (1992) PCNA and Ki67 expression in breast carcinoma: correlations with clinical and biological variables. J Clin Pathol 45:416–419CrossRefPubMedPubMedCentral
10.
go back to reference Al-Dhaheri WS, Hassouna I, Al-Salam S, Karam SM (2008) Characterization of breast cancer progression in the rat. Ann N Y Acad Sci 1138:121–31CrossRefPubMed Al-Dhaheri WS, Hassouna I, Al-Salam S, Karam SM (2008) Characterization of breast cancer progression in the rat. Ann N Y Acad Sci 1138:121–31CrossRefPubMed
11.
go back to reference Bravo R, Frank R, Blundell PA (1987) Cyclin/PCNA is the auxiliary protein of DNA polymerase. Nature 326:515–517CrossRefPubMed Bravo R, Frank R, Blundell PA (1987) Cyclin/PCNA is the auxiliary protein of DNA polymerase. Nature 326:515–517CrossRefPubMed
12.
go back to reference Garikapaty VP, Ashok BT, Tadi K, Mittelman A, Tiwari RK (2006) 3,3′-Diindolylmethane downregulates prosurvival pathway in hormone independent prostate cancer. Biochem Biophys Res Commun 340:718–725CrossRefPubMed Garikapaty VP, Ashok BT, Tadi K, Mittelman A, Tiwari RK (2006) 3,3′-Diindolylmethane downregulates prosurvival pathway in hormone independent prostate cancer. Biochem Biophys Res Commun 340:718–725CrossRefPubMed
13.
go back to reference Nagaraj M, Sunitha S, Varalakshmi P (2000) Effect of lupeol, a pentacyclic triterpene, on the lipid peroxidation and antioxidant status in rat kidney after chronic cadmium exposure. J Appl Toxicol 20:413–417CrossRefPubMed Nagaraj M, Sunitha S, Varalakshmi P (2000) Effect of lupeol, a pentacyclic triterpene, on the lipid peroxidation and antioxidant status in rat kidney after chronic cadmium exposure. J Appl Toxicol 20:413–417CrossRefPubMed
14.
go back to reference Hata K, Hori K, Ogasawara H, Takahashi S (2003) Anti-leukemia activities of lup-28-al-20(29)-en-3-one, a lupane triterpene. Toxicol Lett 143:1–7CrossRefPubMed Hata K, Hori K, Ogasawara H, Takahashi S (2003) Anti-leukemia activities of lup-28-al-20(29)-en-3-one, a lupane triterpene. Toxicol Lett 143:1–7CrossRefPubMed
15.
go back to reference Saleem M, Afaq F, Adhami VM, Mukhtar H (2004) Lupeol modulates NF-kappaB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice. Oncogene 23:5203–5214CrossRefPubMed Saleem M, Afaq F, Adhami VM, Mukhtar H (2004) Lupeol modulates NF-kappaB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice. Oncogene 23:5203–5214CrossRefPubMed
16.
go back to reference Prabhu B, Balakrishnan D, Alwin D, Sundaresan S (2014) Protective Effect of Diindolylmethane against N-Butyl-N-(4-hydroxybutyl) Nitrosamine-induced Bladder Carcinogenesis. J Exp Clin Med 6:132–138CrossRef Prabhu B, Balakrishnan D, Alwin D, Sundaresan S (2014) Protective Effect of Diindolylmethane against N-Butyl-N-(4-hydroxybutyl) Nitrosamine-induced Bladder Carcinogenesis. J Exp Clin Med 6:132–138CrossRef
17.
go back to reference Wanibuchi H, Yamamoto S, Chen H (1996) Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder carcinogenesis in rats. Carcinogenesis 17:2435–2439CrossRefPubMed Wanibuchi H, Yamamoto S, Chen H (1996) Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder carcinogenesis in rats. Carcinogenesis 17:2435–2439CrossRefPubMed
18.
go back to reference Chen I, McDougal A, Wang F (1998) Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis 19:1631–1639CrossRefPubMed Chen I, McDougal A, Wang F (1998) Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis 19:1631–1639CrossRefPubMed
19.
go back to reference Sudharsan PT, Mythili Y, Selvakumar E, Varalakshmi P (2005) Cardioprotective effect of pentacyclic triterpene, lupeol and its ester on cyclophosphamide-induced oxidative stress. Hum Exp Toxicol 24:313–318CrossRefPubMed Sudharsan PT, Mythili Y, Selvakumar E, Varalakshmi P (2005) Cardioprotective effect of pentacyclic triterpene, lupeol and its ester on cyclophosphamide-induced oxidative stress. Hum Exp Toxicol 24:313–318CrossRefPubMed
20.
go back to reference Nakagawa K, Yamamura K, Maeda S (1994) Bcl-2 expression in epidermal keratinocytic diseases. Cancer 74:1720–4CrossRefPubMed Nakagawa K, Yamamura K, Maeda S (1994) Bcl-2 expression in epidermal keratinocytic diseases. Cancer 74:1720–4CrossRefPubMed
21.
go back to reference Lee JH, Khor TO, Shu L (2013) Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacol Ther 137:153–171CrossRefPubMed Lee JH, Khor TO, Shu L (2013) Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacol Ther 137:153–171CrossRefPubMed
22.
go back to reference McKnight JJ, Gray SB, O Kane HF (2005) Apoptosis and chemotherapy for bladder cancer. J Urol 173:683–90CrossRefPubMed McKnight JJ, Gray SB, O Kane HF (2005) Apoptosis and chemotherapy for bladder cancer. J Urol 173:683–90CrossRefPubMed
23.
go back to reference Inagaki T, Ebisuno S, Uekad Y (1997) PCNA and p53 in urinary bladder cancer: correlation with histological findings and prognosis. Int J Urol 4:172–7CrossRefPubMed Inagaki T, Ebisuno S, Uekad Y (1997) PCNA and p53 in urinary bladder cancer: correlation with histological findings and prognosis. Int J Urol 4:172–7CrossRefPubMed
24.
go back to reference Marone M, Scambia G, Mozzetti S (1998) Bcl-2, bax, bcl-XL, and bcl-XS expression in normal and neoplastic ovarian tissues. Clin Cancer Res 4:517–524PubMed Marone M, Scambia G, Mozzetti S (1998) Bcl-2, bax, bcl-XL, and bcl-XS expression in normal and neoplastic ovarian tissues. Clin Cancer Res 4:517–524PubMed
25.
go back to reference Safe S, Papineni S, Chintharlapalli S (2008) Cancer chemotherapy with indole-3-carbinol, bis(3′-indolyl)methane and synthetic analogs. Cancer Lett 269:326–338CrossRefPubMedPubMedCentral Safe S, Papineni S, Chintharlapalli S (2008) Cancer chemotherapy with indole-3-carbinol, bis(3′-indolyl)methane and synthetic analogs. Cancer Lett 269:326–338CrossRefPubMedPubMedCentral
26.
go back to reference Rahman KM (2007) Inactivation of NF-kappaB by 3,3′-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells. Mol Cancer Ther 6:2757–2765CrossRefPubMed Rahman KM (2007) Inactivation of NF-kappaB by 3,3′-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells. Mol Cancer Ther 6:2757–2765CrossRefPubMed
27.
go back to reference Cho HJ, Park SY, Kim EJ (2011) 3,3′-Diindolylmethane inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate model. Mol Carcinogenesis 50:100–12CrossRef Cho HJ, Park SY, Kim EJ (2011) 3,3′-Diindolylmethane inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate model. Mol Carcinogenesis 50:100–12CrossRef
28.
go back to reference Kim YS, Milner JA (2005) Targets for indole-3-carbinol in cancer prevention. J Nutr Biochem 16:65–73CrossRefPubMed Kim YS, Milner JA (2005) Targets for indole-3-carbinol in cancer prevention. J Nutr Biochem 16:65–73CrossRefPubMed
29.
go back to reference Goldberg AA, Titorenko VI, Beach A (2014) Ring-substituted analogs of 3,3′-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and - independent prostate cancer cells. Invest New Drugs 32:25–36CrossRefPubMed Goldberg AA, Titorenko VI, Beach A (2014) Ring-substituted analogs of 3,3′-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and - independent prostate cancer cells. Invest New Drugs 32:25–36CrossRefPubMed
30.
go back to reference Prasad S, Nigam N, Kalra N, Shukla Y (2008) Regulation of signaling pathways involved in lupeol induced inhibition of proliferation and induction of apoptosis in human prostate cancer cells. Mol Carcinogenesis 47:916–24CrossRef Prasad S, Nigam N, Kalra N, Shukla Y (2008) Regulation of signaling pathways involved in lupeol induced inhibition of proliferation and induction of apoptosis in human prostate cancer cells. Mol Carcinogenesis 47:916–24CrossRef
31.
go back to reference Saleem M, Kaur S, Kweon MH (2005) Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway. Carcinogenesis 26:1956–1964CrossRefPubMed Saleem M, Kaur S, Kweon MH (2005) Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway. Carcinogenesis 26:1956–1964CrossRefPubMed
32.
go back to reference Saleem M, Kweon MH, Yun JM (2005) A novel dietary triterpene Lupeol induces fas-mediated apoptotic death of androgen-sensitive prostate cancer cells and inhibits tumor growth in a xenograft model. Cancer Res 65:11203–11213CrossRefPubMed Saleem M, Kweon MH, Yun JM (2005) A novel dietary triterpene Lupeol induces fas-mediated apoptotic death of androgen-sensitive prostate cancer cells and inhibits tumor growth in a xenograft model. Cancer Res 65:11203–11213CrossRefPubMed
33.
go back to reference Palanimuthu D, Baskaran N, Silvan S, Rajasekaran D, Manoharan S (2012) Lupeol, a bioactive triterpene, prevents tumor formation during 7,12-dimethylbenz(a)anthracene induced oral carcinogenesis. Pathol Oncol Res 18(4):1029–37CrossRefPubMed Palanimuthu D, Baskaran N, Silvan S, Rajasekaran D, Manoharan S (2012) Lupeol, a bioactive triterpene, prevents tumor formation during 7,12-dimethylbenz(a)anthracene induced oral carcinogenesis. Pathol Oncol Res 18(4):1029–37CrossRefPubMed
34.
go back to reference Liu Y, Bi T, Wang G (2015) Lupeol inhibits proliferation and induces apoptosis of human pancreatic cancer PCNA-1 cells through AKT/ERK pathways. Naunyn Schmiedebergs Arch Pharmacol 388:295–304CrossRefPubMed Liu Y, Bi T, Wang G (2015) Lupeol inhibits proliferation and induces apoptosis of human pancreatic cancer PCNA-1 cells through AKT/ERK pathways. Naunyn Schmiedebergs Arch Pharmacol 388:295–304CrossRefPubMed
35.
go back to reference Nitta M, Azuma K, Hata K (2013) Systemic and local injections of lupeol inhibit tumor growth in a melanoma-bearing mouse model. Biomed Rep 1:641–645PubMedPubMedCentral Nitta M, Azuma K, Hata K (2013) Systemic and local injections of lupeol inhibit tumor growth in a melanoma-bearing mouse model. Biomed Rep 1:641–645PubMedPubMedCentral
36.
go back to reference Prabhu B, Balakrishnan D, Sundaresan S (2015) Antiproliferative and anti-inflammatory properties of diindolylmethane and lupeol against N-butyl-N-(4-hydroxybutyl) nitrosamine induced bladder carcinogenesis in experimental rats. Hum Exp Toxicol DOI. doi:10.1177/0960327115597985 Prabhu B, Balakrishnan D, Sundaresan S (2015) Antiproliferative and anti-inflammatory properties of diindolylmethane and lupeol against N-butyl-N-(4-hydroxybutyl) nitrosamine induced bladder carcinogenesis in experimental rats. Hum Exp Toxicol DOI. doi:10.​1177/​0960327115597985​
Metadata
Title
Diindolylmethane and Lupeol Modulates Apoptosis and Cell Proliferation in N-Butyl-N-(4-Hydroxybutyl) Nitrosamine Initiated and Dimethylarsinic Acid Promoted rat Bladder Carcinogenesis
Authors
Bhoopathy Prabhu
Annamalai Sivakumar
Sivapatham Sundaresan
Publication date
01-10-2016
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 4/2016
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-016-0054-9

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