Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer

Journal of Experimental & Clinical Cancer Research

Xi-Chun Hu¹  Stefano Fais³  Zhi-Min Shao²  En-Ying Cao¹  Fang-Fang Lv¹  Qun-Ling Zhang¹  Lei-Ping Wang¹  Zhong-Hua Wang¹  Si Sun¹  Jia-Lei Wang¹  Jian Zhang¹  Bi-Yun Wang¹ 

[1] Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China;Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China;Anti-Tumour Drugs Section, Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Rome, Italy

关键词: Overall survival (OS);    Time to progression (TTP);    Chemotherapy;    Metastatic breast cancer;    Proton pump inhibitor;   

Others  :  1226283
DOI  :  10.1186/s13046-015-0194-x

 received in 2015-06-22, accepted in 2015-07-20,  发布年份 2015

【 摘 要 】

Background

Acidity is a hallmark of malignant tumor, representing a very efficient mechanism of chemoresistance. Proton pump inhibitors (PPI) at high dosage have been shown to sensitize chemoresistant human tumor cells and tumors to cytotoxic molecules. The aim of this pilot study was to investigate the efficacy of PPI in improving the clinical outcome of docetaxel + cisplatin regimen in patients with metastatic breast cancer (MBC).

Methods

Patients enrolled were randomly assigned to three arms: Arm A, docetaxel 75 mg/m ²followed by cisplatin 75 mg/m ²on d4, repeated every 21 days with a maximum of 6 cycles; Arm B, the same chemotherapy preceded by three days esomeprazole (ESOM) 80 mg p.o. bid, beginning on d1 repeated weekly. Weekly intermittent administration of ESOM (3 days on 4 days off) was maintained up to maximum 66 weeks; Arm C, the same as Arm B with the only difference being dose of ESOM at 100 mg p.o. bid. The primary endpoint was response rate.

Results

Ninety-four patients were randomly assigned and underwent at least one injection of chemotherapy. Response rates for arm A, B and C were 46.9, 71.0, and 64.5 %, respectively. Median TTP for arm A (n = 32), B (n = 31), C (n = 31) were 8.7, 9.4, and 9.7 months, respectively. A significant difference was observed between patients who had taken PPI and who not with ORR (46.9 % vs. 67.7 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045). Exploratory analysis showed that among 15 patients with triple negative breast cancer (TNBC), this difference was bigger with median TTP of 10.7 and 5.8 months, respectively (p = 0.011). PPI combination showed a marked effect on OS as well, while with a borderline significance (29.9 vs. 19.2 months, p = 0.090). No additional toxicity was observed with PPI.

Conclusions

The results of this pilot clinical trial showed that intermittent high dose PPI enhance the antitumor effects of chemotherapy in MBC patients without evidence of additional toxicity, which requires urgent validation in a multicenter, randomized, phase III trial.

Trial registration

Clinicaltrials.gov identifier: NCT01069081.

【 授权许可】

   
2015 Wang et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

【 参考文献 】

• [1]Martinez-Zaguilan R, Raghunand N, Lynch RM, Bellamy W, Martinez GM, Rojas B, et al.: pH and drug resistance. I. Functional expression of plasmalemmal V-type H + -ATPase in drug-resistant human breast carcinoma cell lines. Biochem Pharmacol 1999, 57:1037-46.
• [2]Mahoney BP, Raghunand N, Baggett B, Gillies RJ: Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. Biochem Pharmacol 2003, 66:1207-18.
• [3]Razaq S, Wilkins RJ, Urban JP: The effect of extracellular pH on matrix turnover by cells of the bovine nucleus pulposus. Eur Spine J 2003, 12:341-9.
• [4]Fais S, De Milito A, You H, Qin W: Targeting vacuolar H + -ATPases as a new strategy against cancer. Cancer Res 2007, 67:10627-30.
• [5]Chiche J, Brahimi-Horn MC, Pouyssegur J: Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med 2010, 14:771-94.
• [6]Vander HM, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324:1029-33.
• [7]Kennedy KM, Dewhirst MW: Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol 2010, 6:127-48.
• [8]Cardone RA, Casavola V, Reshkin SJ: The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer 2005, 5:786-95.
• [9]De Milito A, Fais S: Tumor acidity, chemoresistance and proton pump inhibitors. Future Oncol 2005, 1:779-86.
• [10]Swietach P, Vaughan-Jones RD, Harris AL: Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 2007, 26:299-310.
• [11]Spugnini EP, Citro G, Fais S: Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy. J Exp Clin Cancer Res 2010, 29:44. BioMed Central Full Text
• [12]Nishi T, Forgac M: The vacuolar (H+)-ATPases--nature’s most versatile proton pumps. Nat Rev Mol Cell Biol 2002, 3:94-103.
• [13]Sennoune SR, Bakunts K, Martinez GM, Chua-Tuan JL, Kebir Y, Attaya MN, et al.: Vacuolar H + -ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. Am J Physiol Cell Physiol 2004, 286:C1443-52.
• [14]Fais S: Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. J Intern Med 2010, 267:515-25.
• [15]Luciani F, Spada M, De Milito A, Molinari A, Rivoltini L, Montinaro A, et al.: Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst 2004, 96:1702-13.
• [16]Lu X, Qin W, Li J, Tan N, Pan D, Zhang H, et al.: The growth and metastasis of human hepatocellular carcinoma xenografts are inhibited by small interfering RNA targeting to the subunit ATP6L of proton pump. Cancer Res 2005, 65:6843-9.
• [17]Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, et al.: Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res 2009, 69:2260-8.
• [18]De Milito A, Canese R, Marino ML, Borghi M, Iero M, Villa A, et al.: pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer 2010, 127:207-19.
• [19]Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, et al.: Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res 2012, 72:2746-56.
• [20]Raghunand N, Martinez-Zaguilan R, Wright SH, Gillies RJ: pH and drug resistance. II. Turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs. Biochem Pharmacol 1999, 57:1047-58.
• [21]Raghunand N, He X, van Sluis R, Mahoney B, Baggett B, Taylor CW, et al.: Enhancement of chemotherapy by manipulation of tumour pH. Br J Cancer 1999, 80:1005-11.
• [22]Raghunand N, Mahoney BP, Gillies RJ: Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem Pharmacol 2003, 66:1219-29.
• [23]Fan S, Niu Y, Tan N, Wu Z, Wang Y, You H, et al.: LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump. Oncogene 2013, 32:1682-90.
• [24]von Schwarzenberg K, Lajtos T, Simon L, Muller R, Vereb G, Vollmar AM, et al.: V-ATPase inhibition overcomes trastuzumab resistance in breast cancer. Mol Oncol 2014, 8:9-19.
• [25]You H, Jin J, Shu H, Yu B, De Milito A, Lozupone F, et al.: Small interfering RNA targeting the subunit ATP6L of proton pump V-ATPase overcomes chemoresistance of breast cancer cells. Cancer Lett 2009, 280:110-9.
• [26]Laurencot CM, Andrews PA, Kennedy KA: Inhibitors of intracellular pH regulation induce cisplatin resistance in EMT6 mouse mammary tumor cells. Oncol Res 1995, 7:363-9.
• [27]Murakami T, Shibuya I, Ise T, Chen ZS, Akiyama S, Nakagawa M, et al.: Elevated expression of vacuolar proton pump genes and cellular PH in cisplatin resistance. Int J Cancer 2001, 93:869-74.
• [28]Hinton A, Bond S, Forgac M: V-ATPase functions in normal and disease processes. Pflugers Arch 2009, 457:589-98.
• [29]Der G: An overview of proton pump inhibitors. Gastroenterol Nurs 2003, 26:182-90.
• [30]Metz DC, Forsmark C, Lew EA, Starr JA, Soffer EF, Bochenek W, et al.: Replacement of oral proton pump inhibitors with intravenous pantoprazole to effectively control gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Am J Gastroenterol 2001, 96:3274-80.
• [31]Ramdani A, Mignon M, Samoyeau R: Effect of pantoprazole versus other proton pump inhibitors on 24-hour intragastric pH and basal acid output in Zollinger-Ellison syndrome. Gastroenterol Clin Biol 2002, 26:355-9.
• [32]Mullin JM, Gabello M, Murray LJ, Farrell CP, Bellows J, Wolov KR, et al.: Proton pump inhibitors: actions and reactions. Drug Discov Today 2009, 14:647-60.
• [33]Olbe L, Carlsson E, Lindberg P: A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat Rev Drug Discov 2003, 2:132-9.
• [34]Chen M, Zou X, Luo H, Cao J, Zhang X, Zhang B, et al.: Effects and mechanisms of proton pump inhibitors as a novel chemosensitizer on human gastric adenocarcinoma (SGC7901) cells. Cell Biol Int 2009, 33:1008-19.
• [35]Chen M, Huang SL, Zhang XQ, Zhang B, Zhu H, Yang VW, et al.: Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1alpha/P-gp and MRP1 signaling pathway in vitro and in vivo. J Cell Biochem 2012, 113:2474-87.
• [36]Udelnow A, Kreyes A, Ellinger S, Landfester K, Walther P, Klapperstueck T, et al.: Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells. PLoS One 2011, 6:e20143.
• [37]Ferrari S, Perut F, Fagioli F, Brach DPA, Meazza C, Parafioriti A, et al.: Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. J Transl Med 2013, 11:268. BioMed Central Full Text
• [38]Spugnini EP, Baldi A, Buglioni S, Carocci F, de Bazzichini GM, Betti G, et al.: Lansoprazole as a rescue agent in chemoresistant tumors: a phase I/II study in companion animals with spontaneously occurring tumors. J Transl Med 2011, 9:221. BioMed Central Full Text
• [39]Spugnini EP, Buglioni S, Carocci F, Francesco M, Vincenzi B, Fanciulli M, et al.: High dose lansoprazole combined with metronomic chemotherapy: a phase I/II study in companion animals with spontaneously occurring tumors. J Transl Med 2014, 12:225. BioMed Central Full Text
• [40]De Milito A, Iessi E, Logozzi M, Lozupone F, Spada M, Marino ML, et al.: Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 2007, 67:5408-17.
• [41]Lindner K, Borchardt C, Schopp M, Burgers A, Stock C, Hussey DJ, et al.: Proton pump inhibitors (PPIs) impact on tumour cell survival, metastatic potential and chemotherapy resistance, and affect expression of resistance-relevant miRNAs in esophageal cancer. J Exp Clin Cancer Res 2014, 33:73. BioMed Central Full Text
• [42]Yeo M, Kim DK, Kim YB, Oh TY, Lee JE, Cho SW, et al.: Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells. Clin Cancer Res 2004, 10:8687-96.
• [43]Avnet S, Di Pompo G, Lemma S, Salerno M, Perut F, Bonuccelli G, et al.: V-ATPase is a candidate therapeutic target for Ewing sarcoma. Biochim Biophys Acta 1832, 2013:1105-16.
• [44]Perut F, Avnet S, Fotia C, Baglio SR, Salerno M, Hosogi S, et al. V-ATPase as an effective therapeutic target for sarcomas. Exp Cell Res. 2013.
• [45]Zhang S, Wang Y, Li SJ: Lansoprazole induces apoptosis of breast cancer cells through inhibition of intracellular proton extrusion. Biochem Biophys Res Commun 2014, 448:424-9.
• [46]Goh W, Sleptsova-Freidrich I, Petrovic N: Use of proton pump inhibitors as adjunct treatment for triple-negative breast cancers. An introductory study. J Pharm Pharm Sci 2014, 17:439-46.
• [47]Jin UH, Lee SO, Pfent C, Safe S: The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. BMC Cancer 2014, 14:498. BioMed Central Full Text
• [48]Singh S, Garg SK, Singh PP, Iyer PG, El-Serag HB: Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett’s oesophagus: a systematic review and meta-analysis. Gut 2014, 63:1229-37.
• [49]Kastelein F, Spaander MC, Steyerberg EW, Biermann K, Valkhoff VE, Kuipers EJ, et al.: Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett’s esophagus. Clin Gastroenterol Hepatol 2013, 11:382-8.
• [50]Shamseddine AI, Farhat FS: Platinum-based compounds for the treatment of metastatic breast cancer. Chemotherapy 2011, 57:468-87.
• [51]Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Panopoulos C, Chrissohoou M, et al.: First-line chemotherapy with docetaxel and cisplatin in metastatic breast cancer. Breast 2005, 14:136-41.
• [52]Ahn JH, Kim SB, Sohn HJ, Lee JS, Kang YK, Kun KW: Docetaxel and cisplatin combination chemotherapy in metastatic breast cancer patients with previous exposure to anthracyclines. Breast 2005, 14:304-9.
• [53]Lin YC, Chang HK, Shen WC, Chen JS, Wang HM: An open-labeled phase II trial of docetaxel in combination with cisplatin as first-line cytotoxic therapy for anthracycline-naive patients with metastatic breast cancer. Anticancer Drugs 2007, 18:1213-9.
• [54]Wang YJ, Wu Q, Su FX, Zhou LZ, Ye ZB, Yang JQ, et al.: Phase II study of docetaxel plus epirubicin versus docetaxel plus cisplatin as first-line chemotherapy for advanced breast cancer. Zhonghua Zhong Liu Za Zhi 2008, 30:541-4.
• [55]Fan Y, Xu BH, Yuan P, Ma F, Wang JY, Ding XY, et al.: Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple-negative breast cancer. Ann Oncol 2013, 24:1219-25.
• [56]Sun S, Tang L, Zhang J, Lv F, Wang Z, Wang L, et al.: Cisplatin improves antitumor activity of weekly nab-paclitaxel in patients with metastatic breast cancer. Int J Nanomedicine 2014, 9:1443-52.
• [57]Zhang J, Wang Z, Hu X, Wang B, Wang L, Yang W, et al.: Cisplatin and gemcitabine as the first line therapy in metastatic triple negative breast cancer. Int J Cancer 2015, 136:204-11.
• [58]Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015.
• [59]Korn EL, Arbuck SG, Pluda JM, Simon R, Kaplan RS, Christian MC: Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol 2001, 19:265-72.
• [60]Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA: Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol 2005, 23:7199-206.
• [61]O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002, 20:2812-23.
• [62]Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, et al.: Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2008, 26:3950-7.
• [63]Berrada N, Delaloge S, Andre F: Treatment of triple-negative metastatic breast cancer: toward individualized targeted treatments or chemosensitization? Ann Oncol 2010, 21(Suppl 7):i30-5.
• [64]Perez RP, Hamilton TC, Ozols RF, Young RC: Mechanisms and modulation of resistance to chemotherapy in ovarian cancer. Cancer 1993, 71:1571-80.
• [65]Fujii R, Mutoh M, Niwa K, Yamada K, Aikou T, Nakagawa M, et al.: Active efflux system for cisplatin in cisplatin-resistant human KB cells. Jpn J Cancer Res 1994, 85:426-33.
• [66]Tew KD: Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 1994, 54:4313-20.
• [67]Husain A, He G, Venkatraman ES, Spriggs DR: BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res 1998, 58:1120-3.
• [68]Chaney SG, Sancar A: DNA repair: enzymatic mechanisms and relevance to drug response. J Natl Cancer Inst 1996, 88:1346-60.
• [69]Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, et al.: Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin. PLoS One 2014, 9:e88193.
• [70]Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, et al.: Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 2009, 284:34211-22.
• [71]Logozzi M, De Milito A, Lugini L, Borghi M, Calabrò L, Spada M, et al.: High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One 2009, 4:e5219.