Economopoulou P, Dimitriadis G, Psyrri A. Beyond BRCA: new hereditary breast cancer susceptibility genes. Cancer Treat Rev. 2015;41(1):1–8.
Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26(22):3785–90.
•• Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science. 2017;355(6330):1152–8. Recent concise review on the concept of PARPi use in clinic.
Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, et al. Risks of breast, ovarian, and contralateral breast Cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402–16.
Evers B, Jonkers J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene. 2006;25(43):5885–97.
• Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast Cancer. Clin Cancer Res. 2011;17(5):1082–9. Incidence and relation TNBC and BRCA mutation in breast cancer.
Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomark Prev. 2012;21(1):134–47.
Antoniou AC, Kuchenbaecker KB, Soucy P, Beesley J, Chen X, McGuffog L, et al. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast Cancer Res. 2012;14(1):R33.
Ratnam K, Low JA. Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology. Clin Cancer Res. 2007;13(5):1383–8.
Lord CJ, Ashworth A. Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol. 2008;8(4):363–9.
Pommier Y, O'Connor MJ, de Bono J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med. 2016;8(362):362ps17.
Chaudhuri AR, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol. 2017;18(10):610–21.
Murai J, Huang SYN, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588–99.
McCabe N, Turner NC, Lord CJ, Kluzek K, Białkowska A, Swift S, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109–15.
Lord CJ, Tutt AN, Ashworth A. Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors. Annu Rev Med. 2015;66:455–70.
Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.
Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AOH, Zander SAL, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008;105(44):17079–84.
Xu K, Chen Z, Cui Y, Qin C, He Y, Song X. Combined olaparib and oxaliplatin inhibits tumor proliferation and induces G2/M arrest and γ-H2AX foci formation in colorectal cancer. Onco Targets Ther. 2015;8:3047–54.
Nguewa PA, Fuertes MA, Cepeda V, Alonso C, Quevedo C, Soto M, et al. Poly(ADP-ribose) polymerase-1 inhibitor 3-aminobenzamide enhances apoptosis induction by platinum complexes in cisplatin-resistant tumor cells. Med Chem. 2006;2(1):47–53.
Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13(9):2728–37.
Evers B, Drost R, Schut E, de Bruin M, van der Burg E, Derksen PWB, et al. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin Cancer Res. 2008;14(12):3916–25.
Hastak K, Alli E, Ford JM. Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-ribose) polymerase inhibition, gemcitabine, and cisplatin. Cancer Res. 2010;70(20):7970–80.
Dréan A, Lord CJ, Ashworth A. PARP inhibitor combination therapy. Crit Rev Oncol Hematol. 2016;108:73–85.
Delaney CA, Wang LZ, Kyle S, White AW, Calvert AH, Curtin NJ, et al. Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines. Clin Cancer Res. 2000;6(7):2860–7.
Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13(2):140–56.
Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmañà J, et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2012;2(11):1048–63.
Ibrahim YH, García-García C, Serra V, He L, Torres-Lockhart K, Prat A, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2012;2(11):1036–47.
Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017;17(2):93–115.
Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol. 2014;25(1):32–40.
Booth L, Cruickshanks N, Ridder T, Dai Y, Grant S, Dent P. PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells. Cancer Biol Ther. 2013;14(5):458–65.
Teng YH, et al. Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy. Breast Cancer Res. 2011;13(2):R35.
Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD, Morse D, et al. United States Food and Drug Administration drug approval summary: Gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res. 2004;10(4):1212–8.
Wong SF. Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther. 2005;27(6):684–94.
Sui H, et al. Combination of erlotinib and a PARP inhibitor inhibits growth of A2780 tumor xenografts due to increased autophagy. Drug Des Devel Ther. 2015;9:3183–90.
Farabaugh SM, Boone DN, Lee AV. Role of IGF1R in breast Cancer subtypes, Stemness, and lineage differentiation. Front Endocrinol (Lausanne). 2015;6:59.
Maor S, Yosepovich A, Papa MZ, Yarden RI, Mayer D, Friedman E, et al. Elevated insulin-like growth factor-I receptor (IGF-IR) levels in primary breast tumors associated with BRCA1 mutations. Cancer Lett. 2007;257(2):236–43.
Hudelist G, Wagner T, Rosner M, Fink-Retter A, Gschwantler-Kaulich D, Czerwenka K, et al. Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations. Endocr Relat Cancer. 2007;14(4):1053–62.
Amin O, Beauchamp MC, Nader PA, Laskov I, Iqbal S, Philip CA, et al. Suppression of homologous recombination by insulin-like growth factor-1 inhibition sensitizes cancer cells to PARP inhibitors. BMC Cancer. 2015;15:817.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.
Huang J, Wang L, Cong Z, Amoozgar Z, Kiner E, Xing D, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(−/−) murine model of ovarian cancer. Biochem Biophys Res Commun. 2015;463(4):551–6.
Jiao S, Xia W, Yamaguchi H, Wei Y, Chen MK, Hsu JM, et al. PARP inhibitor upregulates PD-L1 expression and enhances Cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711–20.
Scott CL, Swisher EM, Kaufmann SH. Poly (ADP-ribose) polymerase inhibitors: recent advances and future development. J Clin Oncol. 2015;33(12):1397–406.
Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian Cancer correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512–9.
Matulonis UA, Penson RT, Domchek SM, Kaufman B, Shapira-Frommer R, Audeh MW, et al. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Ann Oncol. 2016;27(6):1013–9.
•• Fong PC, et al. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. New England J Med. 2009;361(2):123–34. Proof of concept trial on PARPi and BRCA mutation, with ovarian and breast cancer patients.
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235–44.
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852–61.
Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al. Olaparib monotherapy in patients with advanced Cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50.
•• Robson M, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. New England Journal of Medicine. 2017;377(6):523–33. First phase III trial of PARPi demonstrating PFS benefit in gBRCAm breast cancer.
Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley M, et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer. 2016;114(7):723–30.
Litton JK, Scoggins M, Ramirez DL, Murthy RK, Whitman GJ, Hess KR, et al. A pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation. Ann Oncol. 2016;27
Turner, N.C., et al., Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO). J Clin Oncol, 2017. 35.
Loibl, S., O'Shaughnessy J., Untch M., Sikov W.M., Rugo H.S., McKee M.D., Huober J., Golshan M., von Minckwitz G., Maag D., Sullivan D., Wolmark N., McIntyre K., Ponce Lorenzo J.J., Metzger Filho O., Rastogi P., Symmans W.F., Liu X., Geyer Jr C.E., Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol, 2018.
• Litton, J., H Ettl, J Hurvitz, S Gonçalves, A Lee, K-H Fehrenbacher, L Yerushalmi, R Mina, L Martin, M Roché, H Im, Y-H Quek, R Tudor, I Hannah, A Eiermann, W Blum, A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physicians choice of therapy in patients with advanced breast cnacer and a germline BRCA mutation., in San Antonio Breast Cancer Symposium. 2017: San Antonio, TX. Early data of Phase III trial of talazoparib, PARPi showing PFS benefit in gBRCAm breast cancer.
Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14(9):882–92.
Dent RA, Lindeman GJ, Clemons M, Wildiers H, Chan A, McCarthy NJ, et al. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first-or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res. 2013;15(5):R88.
Lee J-M, Hays JL, Annunziata CM, Noonan AM, Minasian L, Zujewski JA, et al. Phase I/Ib study of Olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian Cancer with biomarker analyses. Jnci-J Nat Cancer Instit. 2014;106(6)
Lee J-M, Peer CJ, Yu M, Amable L, Gordon N, Annunziata CM, et al. Sequence-specific pharmacokinetic and Pharmacodynamic phase I/Ib study of Olaparib tablets and carboplatin in Women's Cancer. Clin Cancer Res. 2017;23(6):1397–406.
Balmana J, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol. 2014;25(8):1656–63.
Michalarea V, Roda D, Drew Y, Carreira S, O’Carrigan BS, Shaw H, et al. Phase I trial combining the PARP inhibitor olaparib (01a) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations. Cancer Res. 2016;76:CT010.
Miller K, et al. Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple negative breast cancer: final efficacy results of Hoosier oncology group BRE09-146. J Clin Oncol. 2015;33(15)
Wilson RH, Evans TRJ, Middleton MR, Molife LR, Spicer J, Dieras V, et al. A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours. Br J Cancer. 2017;116(7):884–92.
Somlo G, et al. Efficacy of the PARP inhibitor (PI) ABT-888 (veliparib vel ) either with carboplatin (carb) or as a single agent followed by post-progression therapy in combination with carb in patients (pts) with BRCA1- or BRCA2-(BRCA)-associated metastatic breast cancer (MBC). J Clin Oncol. 2015;33(15)
Han HS, Diéras V, Robson M, Palácová M, Marcom PK, Jager A, et al. Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study. Ann Oncol. 2018;29(1):154–61.
Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer L, Buxton MB, et al. Adaptive randomization of Veliparib-carboplatin treatment in breast Cancer. N Engl J Med. 2016;375(1):23–34.
Han HS, Diéras V, Robson ME, Palácová M, Marcom PK, Jager A, et al. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (plc) plus C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: a randomized, phase 2 study. Cancer Res. 2017;77:S2–05.
FDA. Approved Drugs. 2017 December 3rd, 2017.].
EMA. Lynparza / Olaparib. 2015 December 3rd, 2017.].
FDA. Olaparib Label. [Cited 2017 December 3rd, 2017].
Molife LR, et al. Safety and efficacy results from two randomized expansions of a phase I study of a tablet formulation of the PARP inhibitor, olaparib, in ovarian and breast cancer patients with BRCA1/2 mutations. J Clin Oncol. 2012;30(15)
Molife LR, Forster MD, Krebs M, Pwint T, Middleton MR, Kaye SB, et al. A phase I study to determine the comparative bioavailability of two different oral formulations of the PARP inhibitor, olaparib (AZD2281), in patients with advanced solid tumors. J Clin Oncol. 2010;28(15):2599.
Ledermann JA, Drew Y, Kristeleit RS. Homologous recombination deficiency and ovarian cancer. Eur J Cancer. 2016;60:49–58.
Ledermann JA. PARP inhibitors in ovarian cancer. Ann Oncol. 2016;27:40–4.
Ang YLE, Tan DSP. Development of PARP inhibitors in gynecological malignancies. Curr Probl Cancer. 2017;41(4):273–86.
Matulonis UA, Wulf GM, Barry WT, Birrer M, Westin SN, Farooq S, et al. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann Oncol. 2017;28(3):512–8.
Domchek SM, Postel-Vinay S, Bang YJ, Park YH, Alexandre J, Italiano A. Delord JP, You B, Bastian S, Krebs MG, Wang D, Waqar S, Angell HK, and Chung S, Learoyd M, Gresty C, Herbolsheimer P, Kaufman B, An open-label, multitumor, Phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC), in San Antonio Breast Cancer Symposium. 2017: San Antonio, TX.
Lee JM, Gulley JL. Checkpoint and PARP inhibitors, for whom and when. Oncotarget. 2017;8(56):95036–7.
Shen Y, Rehman FL, Feng Y, Boshuizen J, Bajrami I, Elliott R, et al. BMN673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013;19(18):5003–15.
Murai J, Huang SYN, Renaud A, Zhang Y, Ji J, Takeda S, et al. Stereospecific PARP trapping by BMN 673 and comparison with Olaparib and Rucaparib. Mol Cancer Ther. 2014;13(2):433–43.
de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor Talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discovery. 2017;7(6):620–9.
Kohn EC, Lee J-M, Ivy SP. The HRD decision--which PARP inhibitor to use for whom and when. Clin Cancer Res : Off J Am Assoc Cancer Res. 2017;23:7155–7.
Puhalla S, et al. Final results of a phase 1 study of single-agent veliparib (V) in patients (pis) with either BRCA1/2-mutated cancer (BRCA plus ), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt). J Clin Oncol. 2014;32(15)
Kummar S, Ji J, Morgan R, Lenz HJ, Puhalla SL, Belani CP, et al. A phase I study of Veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res. 2012;18(6):1726–34.
Balasubramaniam S, Beaver JA, Horton S, Fernandes LL, Tang S, Horne HN, et al. FDA approval summary: Rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian Cancer. Clin Cancer Res : Off J Am Assoc Cancer Res. 2017;23:7165–70.
Syed YY. Rucaparib: first global approval. Drugs. 2017;77(5):585–92.
Toms C, Chopra N, Houlton L, Jarman K, Kilburn L, Bliss J, et al. Window study of the PARP inhibitor rucaparib in patients with primary triple negative or BRCA1/2 related breast cancer (RIO). Ann Oncol. 2016;27
Scott LJ. Niraparib: First Global Approval. Drugs. 2017;77(9):1029–34.
Konstantinopoulos, P.A., Sachdev J.C., Schwartzberg L., Matulonis U.A., Sun P., Wang J.Y., Guo W., Bobilev D., Aktan G., Karantza V., Dezube B., Vinayak S., Dose-finding combination study of niraparib and pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or recurrent platinum-resistant epithelial ovarian cancer (OC) (TOPACIO/Keynote-162). Ann Oncol, 2017. 28.
Coleman RL, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial (vol 390, pg 1949, 2017). Lancet. 2017;390(10106):1948–8.
Mirza, M.R., et al., A randomized, double-blind phase 3 trial of maintenance therapy with niraparib vs placebo in patients with platinum-sensitive recurrent ovarian cancer (ENGOT-OV16/NOVA trial). Ann Oncol, 2016. 27.
Knezevic CE, Wright G, Remsing Rix LL, Kim W, Kuenzi BM, Luo Y, et al. Proteome-wide profiling of clinical PARP inhibitors reveals compound-specific secondary targets. Cell Chem Biol. 2016;23(12):1490–503.
Lee J-M, Hays JL, Chiou VL, Annunziata CM, Swisher EM, Harrell MI, et al. Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer. Oncotarget. 2017;8(45):79175–87.
Halford SER, et al. Results of the OPARATIC trial: a phase I dose escalation study of olaparib in combination with temozolomide (TMZ) in patients with relapsed glioblastoma (GBM). J Clin Oncol. 2017;35
Mehta MP, Wang D, Wang F, Kleinberg L, Brade A, Robins HI, et al. Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study. J Neuro-Oncol. 2015;122(2):409–17.
Chornenkyy Y, Agnihotri S, Yu M, Buczkowicz P, Rakopoulos P, Golbourn B, et al. Poly-ADP-ribose polymerase as a therapeutic target in pediatric diffuse intrinsic pontine glioma and pediatric high-grade astrocytoma. Mol Cancer Ther. 2015;14(11):2560–8.
Barber LJ, Sandhu S, Chen L, Campbell J, Kozarewa I, Fenwick K, et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J Pathol. 2013;229(3):422–9.
Montoni, A., Robu M., Pouliot É., Shah G.M., Resistance to PARP-inhibitors in cancer therapy. Front Pharmacol, 2013. 4.