ROS mediated DNA damage and induction of apoptosis in cervical cancer cells by Heliotropium indicum L.

Subhabrata Paul; Rita Kundu

doi:10.7324/JAPS.2018.8814

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Abstract

Objective: In Indian sub-continent occurrence of cervical cancer is second among women. Most cervical cancer cases are associated with HPV 16. In this study, the anti-proliferative activity of chloroform fraction of methanolic extract of Heliotropium indicum was studied in a panel of cervical cancer cell lines. Methods: HeLa (HPV 18 positive), SiHa (HPV 16 positive) and C33A (HPV negative) cells were treated with IC50 doses and experiments were performed to evaluate the cell death process. To chemically characterize the extract fraction, GC-MS, LC-MS and column chromatography were performed. Results: Typical apoptotic features were found in the treated cells. Most cells were found in late apoptotic stages. In HeLa and C33A cell lines, cells were blocked at G1/S, in SiHa, subG0 population increased. Expression of anti-apoptotic Bcl-2 decreased and that of pro-apoptotic BAX, p53, p21 increased. Expression of HPV16 and human ET-1 also decreased. ROS mediated DNA damage was detected. Different fatty acids along with other compounds like phenolics, alkaloids were detected in the chloroform fraction, all of which are reported to have anticancer properties. Conclusion: From the study, it can be concluded that fatty acid rich chloroform fraction of H. indicum is capable of inducing apoptosis in cervical cancer cells, through ROS mediated DNA damage.

Keyword: Apoptosis ROS DNA damage Cervical cancer Heliotropium indicum.

Citation:

Paul S, Kundu R. ROS mediated DNA damage and induction of apoptosis in cervical cancer cells by Heliotropium indicum L. J App Pharm Sci, 2018; 8(08): 092-106.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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Carrillo C, Cavia M, Alonso-Torre SR. Antitumor effect of oleic acid; mechanisms of action. A review. Nutricion hospitalaria, 2012; 27(6):1860-5.
Chapkin RS, McMurray DN, Lupton JR. Colon cancer, fatty acids and anti-inflammatory compounds, 2007; 23(1):48-54.
Dash GK, Abdullah MS. A review on Heliotropium indicum L. (Boraginaceae). IJPSR, 2013; 4(4):1253-1258.
Duttagupta S, Dutta PC. Pharmacognostic study of the leaf of Heliotropium indicum. J Crude Drug Res, 1977; 15:141.https://doi.org/10.3109/13880207709055167
Gleeson RP, Ayub M, Wright JT, Wood CB, Habib NA, Soutter WP, et al. Fatty acid control of growth of human cervical and endometrial cancer cells. British journal of cancer, 1990; 61(4):500.https://doi.org/10.1038/bjc.1990.113
Harada H, Yamashita U, Kurihara H, Fukushi E, Kawabata J, Kamei Y. Antitumor activity of palmitic acid found as a selective cytotoxic substance in a marine red alga. Anticancer research, 2002; 22(5):2587-2590.
Hayashi Y, Fukushima S, Hirata T, Kishimoto S, Katsuki T, Nakano M. Anticancer Activity of Free γ-Linolenic Acid on AH-109A Rat Hepatoma Cells and the Effect of Serum Albumin on Anticancer Activity of γ-Linolenic Acid in Vitro. Journal of pharmacobio-dynamics, 1990; 13(11):705-711.https://doi.org/10.1248/bpb1978.13.705
Jimeno A, Rudek MA, Kulesza P, Ma WW, Wheelhouse J, Howard A, et al. Pharmacodynamic-guided modified continuous reassessment method–based, dose-finding study of rapamycin in adult patients with solid tumors. Journal of clinical oncology, 2008; 26(25):4172- 4179.https://doi.org/10.1200/JCO.2008.16.2347
Karra N. Rajanighantu–An important lexicon of pre- Bhavaprakasha era. Ann Ayurvedic Med, 2013; 2(3):104-108.
Lee J, Hwang DH. 2008. Dietary fatty acids and eicosanoids. In: Chow CK, editor. Fatty acids in foods and their Heath Implecations. London, UK: CRC Press 713-39.
Lemic-Stojcevic L, Nias AHW, Breathnach AS. Effect of azelaic acid on melanoma cells in culture. Experimental dermatology, 1995; 4(2):79-81.https://doi.org/10.1111/j.1600-0625.1995.tb00226.x
Oluwatoyin SM, Illeogbulam NG, Joseph A. Phytochemical and antimicrobial studies on the aerial parts of Heliotropium indicum Linn. Annals of Biological Research, 2011; 2(2):129-136.
Paul S, Chakraborty S, Mukherjee A, Kundu R. Evaluation of cytotoxicity and DNA damaging activity of three plant extracts on cervical cancer cell lines. Int J Pharm Sci Rev Res, 2015; 31(1):183-189.
Reddy JS, Rao PR, Reddy Mada S. Wound healing effects of Heliotropium indicum, Plumbago zeylanicum and Acalypha indica inrats. Journal of ethnopharmacology, 2002; 79:249-251.https://doi.org/10.1016/S0378-8741(01)00388-9
Roeder E, Wiedenfeld H. Pyrrolizidine alkaloids in plants used in the traditional medicine of Madagascar and the Mascarene islands. Pharmazie, 2011; 66:637-647.
Sakai M, Kakutani S, Horikawa C, Tokuda H, Kawashima H, Shibata H, et al. Arachidonic acid and cancer risk: a systematic review of observational studies. BMC cancer, 2012; 12(1):606.https://doi.org/10.1186/1471-2407-12-606
Togola A, Diallo D, Dembele S, Barsett H, Paulsen BS. Ethnopharmacological survey of different uses of seven medicinal plants from Mali, (West Africa) in the regions Doila, Kolokani and Siby. Journal of Ethnobiology and Ethnomedicine, 2005; 1:7.https://doi.org/10.1186/1746-4269-1-7
Tsuzuki T, Shibata A, Kawakami Y, Nakagawa K, Miyazawa T. Conjugated eicosapentaenoic acid inhibits vascular endothelial growth factor-induced angiogenesis by suppressing the migration of human umbilical vein endothelial cells. The Journal of nutrition, 2007; 137(3):641- 646.https://doi.org/10.1093/jn/137.3.641
Xavier AP, Santharam L, Panigrahi S, Muthuraman MS, Pemiah B. Antitumor potential of ethanolic extract of Solanum trilobatum against Ehrlich's Ascites Carcinoma. International Journal of Pharm Tech Research, 2013; 5(3):1119-1125.

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Aranda PS, LaJoie DM, Jorcyk CL. Bleach Gel: A Simple Agarose Gel for Analyzing RNA Quality. Electrophoresis, 2012; 33(2):366- 369.https://doi.org/10.1002/elps.201100335

Carrillo C, Cavia M, Alonso-Torre SR. Antitumor effect of oleic acid; mechanisms of action. A review. Nutricion hospitalaria, 2012; 27(6):1860-5.

Chapkin RS, McMurray DN, Lupton JR. Colon cancer, fatty acids and anti-inflammatory compounds, 2007; 23(1):48-54.

Dash GK, Abdullah MS. A review on Heliotropium indicum L. (Boraginaceae). IJPSR, 2013; 4(4):1253-1258.

Duttagupta S, Dutta PC. Pharmacognostic study of the leaf of Heliotropium indicum. J Crude Drug Res, 1977; 15:141.https://doi.org/10.3109/13880207709055167

Gleeson RP, Ayub M, Wright JT, Wood CB, Habib NA, Soutter WP, et al. Fatty acid control of growth of human cervical and endometrial cancer cells. British journal of cancer, 1990; 61(4):500.https://doi.org/10.1038/bjc.1990.113

Harada H, Yamashita U, Kurihara H, Fukushi E, Kawabata J, Kamei Y. Antitumor activity of palmitic acid found as a selective cytotoxic substance in a marine red alga. Anticancer research, 2002; 22(5):2587-2590.

Hayashi Y, Fukushima S, Hirata T, Kishimoto S, Katsuki T, Nakano M. Anticancer Activity of Free γ-Linolenic Acid on AH-109A Rat Hepatoma Cells and the Effect of Serum Albumin on Anticancer Activity of γ-Linolenic Acid in Vitro. Journal of pharmacobio-dynamics, 1990; 13(11):705-711.https://doi.org/10.1248/bpb1978.13.705

Jimeno A, Rudek MA, Kulesza P, Ma WW, Wheelhouse J, Howard A, et al. Pharmacodynamic-guided modified continuous reassessment method–based, dose-finding study of rapamycin in adult patients with solid tumors. Journal of clinical oncology, 2008; 26(25):4172- 4179.https://doi.org/10.1200/JCO.2008.16.2347

Karra N. Rajanighantu–An important lexicon of pre- Bhavaprakasha era. Ann Ayurvedic Med, 2013; 2(3):104-108.

Lee J, Hwang DH. 2008. Dietary fatty acids and eicosanoids. In: Chow CK, editor. Fatty acids in foods and their Heath Implecations. London, UK: CRC Press 713-39.

Lemic-Stojcevic L, Nias AHW, Breathnach AS. Effect of azelaic acid on melanoma cells in culture. Experimental dermatology, 1995; 4(2):79-81.https://doi.org/10.1111/j.1600-0625.1995.tb00226.x

Oluwatoyin SM, Illeogbulam NG, Joseph A. Phytochemical and antimicrobial studies on the aerial parts of Heliotropium indicum Linn. Annals of Biological Research, 2011; 2(2):129-136.

Paul S, Chakraborty S, Mukherjee A, Kundu R. Evaluation of cytotoxicity and DNA damaging activity of three plant extracts on cervical cancer cell lines. Int J Pharm Sci Rev Res, 2015; 31(1):183-189.

Reddy JS, Rao PR, Reddy Mada S. Wound healing effects of Heliotropium indicum, Plumbago zeylanicum and Acalypha indica inrats. Journal of ethnopharmacology, 2002; 79:249-251.https://doi.org/10.1016/S0378-8741(01)00388-9

Roeder E, Wiedenfeld H. Pyrrolizidine alkaloids in plants used in the traditional medicine of Madagascar and the Mascarene islands. Pharmazie, 2011; 66:637-647.

Sakai M, Kakutani S, Horikawa C, Tokuda H, Kawashima H, Shibata H, et al. Arachidonic acid and cancer risk: a systematic review of observational studies. BMC cancer, 2012; 12(1):606.https://doi.org/10.1186/1471-2407-12-606

Togola A, Diallo D, Dembele S, Barsett H, Paulsen BS. Ethnopharmacological survey of different uses of seven medicinal plants from Mali, (West Africa) in the regions Doila, Kolokani and Siby. Journal of Ethnobiology and Ethnomedicine, 2005; 1:7.https://doi.org/10.1186/1746-4269-1-7

Tsuzuki T, Shibata A, Kawakami Y, Nakagawa K, Miyazawa T. Conjugated eicosapentaenoic acid inhibits vascular endothelial growth factor-induced angiogenesis by suppressing the migration of human umbilical vein endothelial cells. The Journal of nutrition, 2007; 137(3):641- 646.https://doi.org/10.1093/jn/137.3.641

Xavier AP, Santharam L, Panigrahi S, Muthuraman MS, Pemiah B. Antitumor potential of ethanolic extract of Solanum trilobatum against Ehrlich's Ascites Carcinoma. International Journal of Pharm Tech Research, 2013; 5(3):1119-1125.