For patients with metastatic prostate cancer, the 5-year survival rate of 31% points to a need for novel therapies and improvement of existing modalities. We propose that p53 gene therapy and chemotherapy, when combined, will provide superior tumor cell killing for the treatment of prostate carcinoma. To this end, we have developed the AdRGD-PGp53 vector which offers autoregulated expression of p53, resulting in enhanced tumor cell killing in vitro and in vivo. Here, we combined AdRGD-PGp53 along with the chemotherapy drugs used in the clinical treatment of prostate carcinoma, mitoxantrone, docetaxel, or cabazitaxel. Our results indicate that all drugs increase phosphorylation of p53, leading to improved induction of p53 targets. In vitro experiments reveal that AdRGD-PGp53 sensitizes prostate cancer cells to each of the drugs tested, conferring increased levels of cell death. In a xenograft mouse model of in situ gene therapy, AdRGD-PGp53 treatment, when combined with cabazitaxel, drastically reduced tumor progression and increased survival rates to 100%. Strikingly, we used a sub-therapeutic dose of cabazitaxel thus avoiding leukopenia, yet still showed potent anti-tumor effects when combined with AdRGD-PGp53 in this mouse model. The AdRGD-PGp53 approach warrants further development for its application in gene therapy of prostate carcinoma.
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Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30.
Debruyne F. Hormonal therapy of prostate cancer. Semin Urol Oncol. 2002;20(3Suppl 1):4–9.
McCullough AR. Sexual dysfunction after radical prostatectomy. Rev Urol. 2005;7(Suppl 2):S3–S10.
Maia MC, Hansen AR. A comprehensive review of immunotherapies in prostate cancer. Crit Rev Oncol Hematol. 2017;113:292–303.
Liu LF. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem. 1989;58:351–75.
Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999;17:1654–63.
Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14:1756–64.
Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002;168:2439–43.
Ernst DS, Tannock IF, Winquist EW, Venner PM, Reyno L, Moore MJ, et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol. 2003;21:3335–42.
Ringel I, Horwitz SB. Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst. 1991;83:288–91.
Schimming R, Mason KA, Hunter N, Weil M, Kishi K, Milas L. Lack of correlation between mitotic arrest or apoptosis and antitumor effect of docetaxel. Cancer Chemother Pharmacol. 1999;43:165–72.
Haldar S, Basu A, Croce CM. Bcl2 is the guardian of microtubule integrity. Cancer Res. 1997;57:229–33.
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–12.
Cisternino S, Bourasset F, Archimbaud Y, Semiond D, Sanderink G, Scherrmann JM. Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood-brain barrier in mice and rats. Br J Pharmacol. 2003;138:1367–75.
Attard G, Greystoke A, Kaye S, De Bono J. Update on tubulin-binding agents. Pathol Biol (Paris). 2006;54:72–84.
de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147–54.
Strauss BE, Costanzi-Strauss E. pCLPG: a p53-driven retroviral system. Virology. 2004;321:165–72.
Bajgelman MC, Strauss BE. Development of an adenoviral vector with robust expression driven by p53. Virology. 2008;371:8–13.
Bajgelman MC, Medrano RF, Carvalho AC, Strauss BE. AAVPG: a vigilant vector where transgene expression is induced by p53. Virology. 2013;447:166–71.
Tamura RE, da Silva Soares RB, Costanzi-Strauss E, Strauss BE. Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy. Cancer Biol Ther. 2016;17:1221–30.
Tamura RE, Hunger A, Fernandes DC, Laurindo FR, Costanzi-Strauss E, Strauss BE. Induction of oxidants distinguishes susceptibility of prostate carcinoma cell lines to p53 gene transfer mediated by an improved adenoviral vector. Hum Gene Ther. 2017;28:639–53.
Merkel CA, Medrano RF, Barauna VG, Strauss BE. Combined p19Arf and interferon-beta gene transfer enhances cell death of B16 melanoma in vitro and in vivo. Cancer Gene Ther. 2013;20:317–25.
Peng HH, Wu S, Davis JJ, Wang L, Roth JA, Marini FC 3rd, et al. A rapid and efficient method for purification of recombinant adenovirus with arginine-glycine-aspartic acid-modified fibers. Anal Biochem. 2006;354:140–7.
Merkel CA, da Silva Soares RB, de Carvalho AC, Zanatta DB, Bajgelman MC, Fratini P, et al. Activation of endogenous p53 by combined p19Arf gene transfer and nutlin-3 drug treatment modalities in the murine cell lines B16 and C6. BMC Cancer. 2010;10:316.
Tomayko MM, Reynolds CP. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 1989;24:148–54.
Radhakrishnan S, Miranda E, Ekblad M, Holford A, Pizarro MT, Lemoine NR, et al. Efficacy of oncolytic mutants targeting pRb and p53 pathways is synergistically enhanced when combined with cytotoxic drugs in prostate cancer cells and tumor xenografts. Hum Gene Ther. 2010;21:1311–25.
Shieh SY, Ikeda M, Taya Y, Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell. 1997;91:325–34.
Loughery J, Cox M, Smith LM, Meek DW. Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters. Nucleic Acids Res. 2014;42:7666–80.
Peng Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther. 2005;16:1016–27.
Guo W, Song H. Development of gene therapeutics for head and neck cancer in china: from bench to bedside. Hum Gene Ther. 2018;29:180–7.
Ko SC, Gotoh A, Thalmann GN, Zhau HE, Johnston DA, Zhang WW, et al. Molecular therapy with recombinant p53 adenovirus in an androgen-independent, metastatic human prostate cancer model. Hum Gene Ther. 1996;7:1683–91.
Asgari K, Sesterhenn IA, McLeod DG, Cowan K, Moul JW, Seth P, et al. Inhibition of the growth of pre-established subcutaneous tumor nodules of human prostate cancer cells by single injection of the recombinant adenovirus p53 expression vector. Int J Cancer J Int du Cancer. 1997;71:377–82.
Eastham JA, Hall SJ, Sehgal I, Wang J, Timme TL, Yang G, et al. In vivo gene therapy with p53 or p21 adenovirus for prostate cancer. Cancer Res. 1995;55:5151–5.
Tamura RE, Hunger A, Fernandes D, Laurindo F, Costanzi-Strauss E, Strauss BE Induction of oxidants distinguishes susceptibility of prostate carcinoma cell lines to p53 gene transfer mediated by an improved adenoviral vector. Hum Gene Ther 2017;28:639-53.
Sasaki R, Shirakawa T, Zhang ZJ, Tamekane A, Matsumoto A, Sugimura K, et al. Additional gene therapy with Ad5CMV-p53 enhanced the efficacy of radiotherapy in human prostate cancer cells. Int J Radiat Oncol Biol Phys. 2001;51:1336–45.
Cowen D, Salem N, Ashoori F, Meyn R, Meistrich ML, Roth JA, et al. Prostate cancer radiosensitization in vivo with adenovirus-mediated p53 gene therapy. Clin Cancer Res. 2000;6:4402–8.
Gjerset R, Haghighi A, Lebedeva S, Mercola D. Gene therapy approaches to sensitization of human prostate carcinoma to cisplatin by adenoviral expression of p53 and by antisense jun kinase oligonucleotide methods. Methods Mol Biol. 2001;175:495–520.
Chuang JC, Sheu GT, Wang PC, Liao FT, Liu WS, Huang CF, et al. Docetaxel and 5-fluorouracil induce human p53 tumor suppressor gene transcription via a short sequence at core promoter element. Toxicol Vitr. 2012;26:678–85.
Liu C, Zhu Y, Lou W, Nadiminty N, Chen X, Zhou Q, et al. Functional p53 determines docetaxel sensitivity in prostate cancer cells. Prostate. 2013;73:418–27.
Gan L, Wang J, Xu H, Yang X. Resistance to docetaxel-induced apoptosis in prostate cancer cells by p38/p53/p21 signaling. Prostate. 2011;71:1158–66.
Nozawa M, Mukai H, Takahashi S, Uemura H, Kosaka T, Onozawa Y, et al. Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer. Int J Clin Oncol. 2015;20:1026–34.
Heidenreich A, Bracarda S, Mason M, Ozen H, Sengelov L, Van Oort I, et al. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: results of the European compassionate-use programme. Eur J Cancer. 2014;50:1090–9.
We thank Roger Chammas and his staff for ongoing support and critical discussions. We thank Otto Luiz Dutra Cerqueira for assistance during the preparation of this manuscript. This work was a collaborative effort with Sanofi-Aventis which facilitated the purchase of the cabazitaxel used here.
Financial support was received from the São Paulo Research Foundation, FAPESP (RET, 2011/21256–8; BES, 2013/25167–5 and 2015/26580–9) and from Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq (RET, 442738/2014–5; 302888/2017–9, BES). Financial support was provided by Sanofi-Aventis (ISS PRECLL 06945) in order to obtain the cabazitaxel used in this study.
Conflict of interest
The authors declare that they have no conflict of interest.
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