Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells

Apoptosis

Volumn 17, Issue 9, 2012, Pages 989-997

  Kang, Sokbom ^a   Dong, Seung Myung ^a   Kim, Boh Ram ^a   Park, Mi Sun ^a   Trink, Barry ^b   Byun, Hyun Jung ^a   Rho, Seung Bae ^a  

^a National Cancer Center   (South Korea)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Anti cancer activity; Apoptosis; Cervical tumorigenesis; mTOR signaling; Thioridazine

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; CISPLATIN; CYCLIN A; CYCLIN D1; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE INHIBITOR; INITIATION FACTOR 4E BINDING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN P21; PROTEIN P27; PROTEIN SERINE THREONINE KINASE; S6 KINASE; THIORIDAZINE; WORTMANNIN;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER CELL; CANCER CELL CULTURE; CANCER INHIBITION; CELL CYCLE ARREST; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOWN REGULATION; ENDOMETRIUM CANCER; GENE TARGETING; HUMAN; HUMAN TISSUE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; UTERINE CERVIX CANCER;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANTINEOPLASTIC AGENTS; APOPTOSIS; CASPASE 3; CELL DIVISION; CELL LINE, TUMOR; CELL SURVIVAL; CYCLIN A; CYCLIN D1; CYCLIN-DEPENDENT KINASE 4; CYCLIN-DEPENDENT KINASE INHIBITOR P21; CYCLIN-DEPENDENT KINASE INHIBITOR P27; DOWN-REGULATION; ENDOMETRIAL NEOPLASMS; FEMALE; HELA CELLS; HUMANS; PHOSPHATIDYLINOSITOL 3-KINASES; PHOSPHOPROTEINS; PHOSPHORYLATION; PROTO-ONCOGENE PROTEINS C-AKT; RIBOSOMAL PROTEIN S6 KINASES, 70-KDA; SIGNAL TRANSDUCTION; THIORIDAZINE; TOR SERINE-THREONINE KINASES; UTERINE CERVICAL NEOPLASMS;

EID: 84865126692     PISSN: 13608185     EISSN: 1573675X     Source Type: Journal    
DOI: 10.1007/s10495-012-0717-2     Document Type: Article

References (39)

1. Cowap J, Hardy J (1998) Thioridazine in the management of cancer-related sweating. J Pain Symptom Manag 15:266
2. Zhukovsky DS (2002) Fever and sweats in the patient with advanced cancer. Hematol Oncol Clin North Am 16:579-588 (Pubitemid 34827369)
3. Ly KL, Chidgey J, Addington-Hall J et al (2002) Depression in palliative care: a systematic review. Part 2 treatment. Palliat Med 16:279-284 (Pubitemid 34785124)
4. Ramu A, Spanier R, Rahamimoff H et al (1984) Restoration of doxorubicin responsiveness in doxorubicin-resistant P388 murine leukaemia cells. Br J Cancer 50:501-507 (Pubitemid 14015592)
5. Akiyama S, Shiraishi N, Kuratomi Y et al (1986) Circumvention of multiple-drug resistance in human cancer cells by thioridazine, trifluoperazine, and chlorpromazine. J Natl Cancer Inst 76:839-844 (Pubitemid 16121940)
6. Munyon WH, Salo R, Briones DF (1987) Cytotoxic effects of neuroleptic drugs. Psychopharmacology 91:182-188 (Pubitemid 17002270)
7. Strobl JS, Kirkwood KL, Lantz TK (1990) Inhibition of human breast cancer cell proliferation in tissue culture by the neuroleptic agents pimozide and thioridazine. Cancer Res 50:5399-5405 (Pubitemid 20302995)
8. Glass-Marmor L, Morgenstern H, Beitner R (1996) Calmodulin antagonists decrease glucose 1,6-bisphosphate, fructose 1,6-bisphosphate, ATP and viability of melanoma cells. Eur J Pharmacol 313:265-271 (Pubitemid 26345988)
9. 3H]azidopine photolabeling of P-glycoprotein by newly synthesized dihydropyridine analogues in a human cell line. Cancer Res 49:3190-3195 (Pubitemid 19162123)
10. Pantazaki AA, Lialiaris TS (1999) A combined biochemical and cytogenetic study of thioridazine-induced damage to nucleic acids. Mutagenesis 14:243-248 (Pubitemid 29123792)
11. Rodrigues T, Santos AC, Pigoso AA et al (2002) Thioridazine interacts with the membrane of mitochondria acquiring antioxidant activity toward apoptosis-potentially implicated mechanisms. Br J Pharmacol 136:136-142 (Pubitemid 34499326)
12. Basta-Kaim A, Budziszewska B, Jagła G et al (2006) Inhibitory effect of antipsychotic drugs on the Con A- and LPS-induced proliferative activity of mouse splenocytes: a possible mechanism of action. J Physiol Pharmacol 57:247-264 (Pubitemid 44077749)
13. Lamb J, Crawford ED, Peck D et al (2006) The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313:1929-1935 (Pubitemid 44497995)
14. Franke TF, Hornik CP, Segev L et al (2003) PI3K/Akt and apoptosis: size matters. Oncogene 22:8983-8998 (Pubitemid 38121699)
15. Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240-4245 (Pubitemid 29190320)
16. Yang X, Fraser M, Moll UM et al (2006) Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway. Cancer Res 66:3126-3136
17. Altomare DA, Wang HQ, Skele KL et al (2004) AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 23:5853-5857 (Pubitemid 39093031)
18. Franke TF, Kaplan DR, Cantley LC et al (1997) Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 275:665-668 (Pubitemid 27061333)
19. Vanhaesebroeck B, Waterfield MD (1999) Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res 253:239-254
20. Yuan ZQ, Sun N, Feldman RI et al (2000) Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene 19:2324-2330 (Pubitemid 30307208)
21. Bjornsti MA, Houghton PJ (2004) The mTOR pathways: a target for cancer therapy. Nat Rev Cancer 4:335-348 (Pubitemid 38579480)
22. Bjornsti MA, Houghton PJ (2004) Lost in translation: dysregulation of cap-dependent translation and cancer. Cancer Cell 5:519-523 (Pubitemid 38748913)
23. Zhang J, Snyder SH (1992) Nitric oxide stimulates auto-ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci USA 89:9382-9385
24. Zhang J (1997) Use of biotinylated NAD to label and purify ADP-ribosylated proteins. Methods Enzymol 280:255-265 (Pubitemid 28182362)
25. Fruman DA, Mauvais-Jarvis F, Pollard DA (2000) Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nat Genet 26:379-382
26. Rho SB, Kim BR, Kang S (2011) A gene signature-based approach identifies thioridazine as an inhibitor of phosphatidylinositol-3'-kinase (PI3K)/AKT pathway in ovarian cancer cells. Gynecol Oncol 120:121-127
27. Wan X, Harkavy B, Shen N et al (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26:1932-1940 (Pubitemid 46474636)
28. Kandel ES, Hay N (1999) The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res 253:210-229
29. Blanco-Aparicio C, Renner O, Leal JF et al (2007) PTEN, more than the AKT pathway. Carcinogenesis 28:1379-1386 (Pubitemid 47243536)
30. Hu L, Hofmann J, Jaffe RB (2005) Phosphatidylinositol 3-kinase mediates angiogenesis and vascular permeability associated with ovarian carcinoma. Clin Cancer Res 11:8208-8212 (Pubitemid 41698766)
31. Hu L, Zaloudek C, Mills GB et al (2000) In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res 6:880-886 (Pubitemid 30159344)
32. Mabuchi S, Altomare DA, Cheung M et al (2007) RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 13:4261-4270 (Pubitemid 47105991)
33. Mabuchi S, Kawase C, Altomare DA et al (2009) mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary. Clin Cancer Res 15:5404-5413
34. Shi Y, Frankel A, Radvanyi LG et al (1995) Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res 55:1982-1988
35. Fingar DC, Salama S, Tsou C et al (2002) Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 16:1472-1487 (Pubitemid 34686329)
36. Gil-Ad I, Shtaif B, Levkovitz Y et al (2006) Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth. Oncol Rep 15:107-112
37. Hercbergs A (1988) Thioridazine: a radiation enhancer in advanced cervical cancer? Lancet 2:737
38. Axelsson R, Martensson E, Alling C (1982) Serum concentration and protein binding of thioridazine and its metabolites in patients with chronic alcoholism. Eur J Clin Pharmacol 23:359-363 (Pubitemid 13229990)
39. Csatary LK (1972) Chlorpromazines and cancer. Lancet 2:338-339