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Investigational New Drugs
Published in: Investigational New Drugs 2/2013

01-04-2013 | PRECLINICAL STUDIES

Enhanced killing of cervical cancer cells by combinations of methyl jasmonate with cisplatin, X or alpha radiation

Authors: Elad Milrot, Anna Jackman, Eliezer Flescher, Pinhas Gonen, Itzhak Kelson, Yona Keisari, Levana Sherman

Published in: Investigational New Drugs | Issue 2/2013

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Summary

Current therapies for treatment of advanced cervical cancer involve the use of cisplatin, often in combination with radiotherapy. These treatments do not lead to a high survival rate and furthermore, serious side effects are dose-limiting factors. Methyl jasmonate (MJ) was recently identified as potent and selective cytotoxic agent towards cervical cancer cells. In the present study we evaluated the effectiveness of combined treatments of MJ with cisplatin or X-irradiation on a variety of cervical cancer cells including SiHa, CaSki, HeLa and C33A. Cytotoxicity of alpha particles, emitted from 224Ra atoms, was also evaluated as a single agent and in combination with MJ. Cooperation between MJ and cisplatin in reducing cell viability (XTT assays) and survival (clonogenicity assays) was exhibited towards several cancer cell lines at a range of combination doses. MJ effectively cooperated also with X-ray irradiation, significantly lowering the radiation doses required to inhibit cell survival (ID50) of all tested cells lines. We show for the first time, that alpha irradiation selectively reduced cell viability and survival of cervical cancer cells. Lower doses of α irradiation were required as compared to X-irradiation to inhibit cell survival. Cooperation with MJ was demonstrated in part of the cancer cell lines. In conclusion, our studies point to α irradiation and MJ, novel anticancer agents, as potent candidates for treatment of cervical cancer, in single agent regiments and in combination. MJ can be added also to conventional X-ray and cisplatin therapies to increase their cytotoxic effect while lowering the effective dose.
Literature
1.
2.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90PubMedCrossRef
3.
Steben M, Duarte-Franco E (2007) Human papillomavirus infection: epidemiology and pathophysiology. Gynecol Oncol 107(Suppl 1):S2–S5PubMedCrossRef
4.
5.
Schiller JT, Castellsague X, Villa LL, Hildesheim A (2008) An update of prophylactic human papillomavirus L1 virus-like particle vaccine clinical trial results. Vaccine 26(Suppl 10):K53–K61PubMedCrossRef
6.
Lin K, Doolan K, Hung CF, Wu TC (2010) Perspectives for preventive and therapeutic HPV vaccines. J Formos Med Assoc 109(1):4–24PubMedCrossRef
7.
Movva S, Rodriguez L, Arias-Pulido H, Verschraegen C (2009) Novel chemotherapy approaches for cervical cancer. Cancer 115(14):3166–3180PubMedCrossRef
8.
Serkies K, Jassem J (2005) Chemotherapy in the primary treatment of cervical Carcinoma. Crit Rev Oncol Hematol 54(3):197–208PubMedCrossRef
9.
Maduro JH, Pras E, Willemse PH, de Vries EGE (2003) Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer. Cancer Treat Rev 29(6):471–488PubMedCrossRef
10.
Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22(47):7265–7279PubMedCrossRef
11.
Savarese A, Cognetti F (2003) New Drugs in the treatment of recurrent or metastatic cervical cancer. Crit Rev Oncol Hematol 48(3):323–327PubMedCrossRef
12.
Hougardy BM, Maduro JH, Vander Zee AGJ, Willemse PHB, deJong S, de Vries EGE (2005) Clinical potential of inhibitors of survival pathways and activators of apoptotic pathways in treatment of cervical cancer: changing the apoptotic balance. Lancet Oncol 6(8):589–598PubMedCrossRef
13.
14.
Cohen S, Flescher E (2009) Methyl jasmonate: a plant stress hormone as an anti-cancer drug. Phytochemistry 70(13–14):1600–1609PubMedCrossRef
15.
Rotem R, Heyfets A, Fingrut O, Blickstein D, Shaklai M, Flescher E (2005) Jasmonates: novel anticancer agents acting directly and selectively on human cancer cell mitochondria. Cancer Res 65(5):1984–1993PubMedCrossRef
16.
Kniazhanski T, Jackman A, Heyfets A, Gonen P, Flescher E, Sherman L (2008) Methyl jasmonate induces cell death with mixed characteristics of apoptosis and necrosis in cervical cancer cells. Cancer Lett 271(1):34–46PubMedCrossRef
17.
Milrot E, Jackman A, Kniazhanski T, Gonen P, Flescher E, Sherman L (2012) Methyl jasmonate reduces the survival of cervical cancer cells and downregulates HPV E6 and E7, and survivin. Cancer Lett 319(1):31–38PubMedCrossRef
18.
Takimoto C, Calvo E (2005) Principles of oncologic pharmacotherapy. In: Pazdur R, Coia LR, Hoskins WJ, Wagman LD (eds) Cancer management: a multidisciplinary approach. CMP Healthcare Media, Manhasset, pp 23–42
19.
Heyfets A, Flescher E (2007) Cooperative cytotoxicity of methyl jasmonate with anti-cancer drugs and 2-deoxy-D-glucose. Cancer Lett 250(2):300–310PubMedCrossRef
20.
Yeruva L, Hall C, Abiodun J, Elegbede JA, Carper SW (2010) Perillyl alcohol and methyl jasmonate sensitize cancer cells to cisplatin. Anticancer Drugs 21(1):1–9PubMedCrossRef
21.
Ezekwudo D, Shashidharamurthy R, Devineni D, Bozeman E, Palaniappan R, Selvaraj P (2008) Inhibition of expression of anti-apoptotic protein Bcl-2 and induction of cell death in radioresistant human prostate adenocarcinoma cell line (PC-3) by methyl jasmonate. Cancer Lett 270(2):277–285PubMedCrossRef
22.
Arazi L, Cooks T, Schmidt M, Keisari Y, Kelson I (2007) Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters. Phys Med Biol 52(16):5025–5042PubMedCrossRef
23.
Cooks T, Arazi L, Schmidt M, MarshakG KI, Keisari Y (2008) Growth retardation and destruction of experimental squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms. Int J Cancer 122(7):1657–1664PubMedCrossRef
24.
Cooks T, Schmidt M, Bittan H, Lazarov E, Arazi L, Kelson I, Keisari Y (2009) Local control of lung derived tumors by diffusing alpha-emitting atoms released from intratumoral wires loaded with radium-224. Int J Radiat Oncol Biol Phys 74(3):966–973PubMedCrossRef
25.
Horev-Drori G, Cooks T, Bittan H, Lazarov E, Scmidt M, Arazi L, Efrati M, Kelson I, Keisari Y (2012) Local control of malignant pancreatic tumors by a combined treatment with intratumoral 225Radium-loaded wires releasing alpha-emitting atoms and chemotherapy. Transl Res 159(1):32–41PubMedCrossRef
26.
Lazarov E, Arazi L, Efrati M, Crooks T, Scmidt M, Keisari Y, Kelson I (2012) Comparative in vitro microdosimetric study of murine-and human-derived cancer cells exposed to alpha particles. Radiat Res 177(3):280–287PubMedCrossRef
27.
Alfandari J, Shnitman Magal S, Jackman A, Schlegel R, Gonen P, Sherman L (1999) HPV16 E6 oncoprotein inhibits apoptosis induced during serum-calcium differentiation of foreskin human keratinocytes. Virology 257(2):383–396PubMedCrossRef
28.
Zhao L, Wientjes MG, Au JL (2004) Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram and combination index analyses. Clin Cancer Res 10(23):7994–8004PubMedCrossRef
29.
Cullen KJ, Yang Z, Schumaker L, Guo Z (2007) Mitochondria as a critical target of the chemotherapeutic agent cisplatin in head and neck cancer. J Bioenerg Biomembr 39(1):43–50PubMedCrossRef
30.
Ahamad A, Jhingran A (2004) New radiation techniques in gynecological cancer. Int J Gynecol Cancer 14(4):569–579PubMedCrossRef
31.
Mauceri HJ, Hanna NN, Beckett MA, Gorski DH, Staba MJ, Stellato KA, Bigelow K, Heimann R, Gately S, Dhanabal M, Soff GA, Sukhatme VP, Kufe DW, Weichselbaum RR (1998) Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 394(6690):287–291PubMedCrossRef
32.
Katzung BG (1998) Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, analgesics, and drugs nonopioid used in gout. In: Katzung BG (ed) Basic and clinical pharmacology. Appleton & Lange, Stamford (CT), pp 578–602
33.
Pouget JP, Mather SJ (2001) General aspects of the cellular response to low- and high-LET radiation. Eur J Nucl Med 28(4):541–561PubMedCrossRef
34.
Mori E, Takahashi A, Yamakawa N, Kirita T, Ohnishi T (2009) High LET heavy ion radiation induces p53-independent apoptosis. J Radiat Res 50(1):37–42PubMedCrossRef
Metadata
Title
Enhanced killing of cervical cancer cells by combinations of methyl jasmonate with cisplatin, X or alpha radiation
Authors
Elad Milrot
Anna Jackman
Eliezer Flescher
Pinhas Gonen
Itzhak Kelson
Yona Keisari
Levana Sherman
Publication date
01-04-2013
Publisher
Springer US
Published in
Investigational New Drugs / Issue 2/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-012-9870-2

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