A phase I trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors: evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin

Braña, Irene; Ocaña, Alberto; Chen, Eric X.; Razak, Albiruni R. Abdul; Haines, Christine; Lee, Carol; Douglas, Sarah F.; Wang, Lisa; Siu, Lillian L.; Tannock, Ian F.; Bedard, Philippe L.

doi:10.1007/s10637-014-0159-5

Cited by 46 publications

(22 citation statements)

References 34 publications

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“…There are examples of clinical trials aiming to increase the effectiveness of chemotherapy via a combination of a basic drug such as doxorubicin and a PPI. Pantoprazole in combination with doxorubicin was concluded to be feasible in a phase I trial in various solid tumors not including lung cancer (Brana et al, 2014). Real-time cytotoxicity data were obtained from the xCELLigence system that gives information about whether a compound has antiproliferative, cytostatic, or cytotoxic effects at a particular dose and time point.…”

Section: Discussionmentioning

confidence: 99%

Combination of esomeprazole with chemotherapeutics results in more pronounced cytotoxic effect via apoptosis on A549 nonsmall-cell lung cancer cell line

Oral¹,

Oral²,

Sarimahmut³

et al. 2017

Turk J Biol

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IntroductionLung cancer ranks first in deaths among malignancies and approximately 1.59 million people (19.4% of all cancer deaths excluding nonmelanoma skin cancer) die worldwide from lung cancer every year (Ferlay et al., 2013). The 5-year survival rate for nonsmall-cell lung cancer is estimated to be 10.5% for females and 9.4% for males (Caldarella et al., 2007). No symptoms are detected in the early stage of most lung cancer cases, which results in late diagnosis (Carter-Harris et al., 2014;Shim et al., 2014). Despite the recently developed diagnostic methods, the localization of detected tumors is not limited to the lungs. The most important difficulty in lung cancer therapy is metastasis to different organs or different sites in the lung, which makes it almost impossible to fully eradicate the tumor by surgery, radiotherapy, and chemotherapy. Hence, resistance to chemotherapeutics becomes crucial in patients with no chance of curative surgery.The acidity of the tumor microenvironment is one of the important factors in chemotherapy resistance. The vacuolar (H + )-ATPases (V-ATPases) that pump H + from the cytoplasm to extracellular compartments have a critical role in acidity (Perez-Sayans et al., 2009). These multisubunit V-ATPase complexes are basically expressed in all eukaryotic cells, although there are variations in subunits (Wagner et al., 2004). However, they are preferentially expressed in various cancer types including pancreatic cancer, oral squamous cell cancer, and nonsmall-cell lung carcinoma compared to nonmalignant tissues, and higher expression levels of V-ATPases are linked to malignant phenotypes (Sennoune et al., 2004;Chung et al., 2011;Garcia-Garcia et al., 2012;Qiang et al., 2013). Consequently, therapeutic approaches to inhibit V-ATPases are expected to increase sensitivity towards antineoplastic agents or overcome chemoresistance.Tumor tissues, and especially solid tumors, possess different microenvironmental features (Vaupel, 2004). The

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Section: Discussionmentioning

confidence: 99%

Combination of esomeprazole with chemotherapeutics results in more pronounced cytotoxic effect via apoptosis on A549 nonsmall-cell lung cancer cell line

Oral¹,

Oral²,

Sarimahmut³

et al. 2017

Turk J Biol

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“…Pantoprazole has been found to enhance activity of docetaxel against human tumor xenografts by inhibiting autophagy [234]. Furthermore, pantoprazole is also in clinical trials for treatment of advanced solid tumors in combination with doxorubicin [235]. These studies suggest that inhibitors of proton transporters may have potential for cancer prevention or treatment.…”

Section: Implications For Cancer Therapy and Chemopreventionmentioning

confidence: 99%

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

Justus

Sanderlin

Yang

2015

IJMS

115

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Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention.

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“…[18–20] Therefore, repositioning PPIs as anticancer drugs will be unlikely to have added toxicities. Although PPIs has been proposed as the adjuvant drugs for cancer treatment, and even a clinical trial was performed to evaluate the use of pantoprazole in combination with doxorubicin for advanced cancer patients with solid tumors [21, 22]. However, whether PPIs directly suppress tumor growth remained to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Chemical structures of prazoles were input as mol2 files for docking [21]. The docking was performed by using ICM 3.8.1 modeling software on an Intel i7 4960 processor (MolSoft LLC, San Diego, CA) [27].…”

Section: Methodsmentioning

confidence: 99%

Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase

et al. 2017

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T-cell-originated protein kinase (TOPK) is highly and frequently expressed in various cancer tissues and plays an indispensable role in the mitosis of cancer cells, and therefore, it is an important target for drug treatment of tumor. Ilaprazole was identified to be a potent TOPK inhibitor. The data indicated that ilaprazole inhibited TOPK activities with high affinity and selectivity. In vitro studies showed that ilaprazole inhibited TOPK activities in HCT116, ES-2, A549, SW1990 cancer cells. Moreover, knockdown of TOPK in these cells decreased their sensitivities to ilaprazole. Results of an in vivo study demonstrated that gavage of ilaprazole in HCT116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after ilaprazole treatment. Our results suggested that ilaprazole inhibited the cancer growth by targeting TOPK both in vitro and in vivo.

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A phase I trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors: evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin

Abstract: Administration of high doses of pantoprazole in combination with doxorubicin is feasible. The recommended phase II dose of pantoprazole, 240 mg, will be evaluated in combination with docetaxel as first line in patients with castration-resistant prostate cancer.

Cited by 46 publications

References 34 publications

Combination of esomeprazole with chemotherapeutics results in more pronounced cytotoxic effect via apoptosis on A549 nonsmall-cell lung cancer cell line

Combination of esomeprazole with chemotherapeutics results in more pronounced cytotoxic effect via apoptosis on A549 nonsmall-cell lung cancer cell line

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase

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