Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models

Balza, Enrica; Carlone, Sebastiano; Carta, Sonia; Piccioli, Patrizia; Cossu, Vanessa; Marini, Cecilia; Sambuceti, Gianmario; Rubartelli, Anna; Castellani, Patrizia

doi:10.1002/cam4.4371

Cited by 4 publications

(3 citation statements)

References 51 publications

(118 reference statements)

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“…In our study, we found that only Lansoprazole was effective in delaying tumor growth and this efficacy was associated with a marked and prolonged reduction in the extracellular tumor acidification, demonstrating the in vivo inhibitory effectiveness of this drug. Recently, another V-ATPase inhibitor, Esomeprazole, demonstrated a remarkable reduced tumor growth and increased survival in the 4T1 TNBC murine model, although tumor pH was not evaluated [73].…”

Section: Discussionmentioning

confidence: 99%

“…Amiloride, an NHE1 inhibitor, has been shown to provide a moderate cell toxicity in human melanoma cancer cells, although it was ineffective in delaying melanoma tumor growth [74]. In breast cancer cells, only Amiloride derivatives have been investigated, with a modest cell toxicity in both murine and human cell lines, but a single treatment with this Amiloride derivative (EIPA) was less effective in reducing the tumor growth rate than the treatment with cisplatin alone [73,75]. Also in the present study, mice displayed no detectable reduction in tumor growth rate, although a moderate toxicity was observed in cellular experiments.…”

Section: Discussionmentioning

confidence: 99%

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Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging—Chemical Exchange Saturation Transfer Tumor pH Imaging

Dhakan,

Anemone,

Ventura

et al. 2023

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Proton transporters play a key role in maintaining the acidic tumor microenvironment; hence, their inhibition has been proposed as a new therapeutic treatment, although few methods can accurately assess their effect in vivo. In this study, we investigated whether MRI-CEST (Magnetic Resonance Imaging—Chemical Exchange Saturation Transfer) tumor pH imaging can be a useful tool to evaluate in vivo the therapeutic efficacy of several Proton Pump Inhibitors (PPIs) in breast cancer. Cell viability and extracellular pH assays were carried out in breast cancer cells cultured at physiological pH (7.4) or acid-adapted (pH of 6.5 and 6.8) following the exposure to inhibitors of V-ATPase (Lansoprazole, Esomeprazole) or NHE1 (Amiloride, Cariporide) at several concentrations. Next, triple-negative breast cancer 4T1 tumor-bearing mice were treated with Lansoprazole or Amiloride and MRI-CEST tumor pH imaging was utilized to assess the in vivo efficacy. Only Lansoprazole induced, in addition to breast cancer cell toxicity, a significant inhibition of proton extrusion. A significant reduction in tumor volume, prolonged survival, and increase in extracellular tumor pH after 1 and 2 weeks were observed after Lansoprazole treatment, whereas no significant changes were detected upon Amiloride treatment. Our results suggested that MRI-CEST tumor pH imaging can monitor the therapeutic efficacy of PPIs in breast cancer murine models.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging—Chemical Exchange Saturation Transfer Tumor pH Imaging

Dhakan,

Anemone,

Ventura

et al. 2023

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“…The MDR problem has even further complexities. Balza et al [ 238 ] , working with two different breast cancer cells, a triple-negative one and a hormone-sensitive one, found that:…”

Section: Discussionmentioning

confidence: 99%

The complex relationship between multiple drug resistance and the tumor pH gradient: a review

Koltai¹

2022

Cancer Drug Resist

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Multiple drug resistance (MDR) is the tumor’s way of escaping the cytotoxic effects of various unrelated chemotherapeutic drugs. It can be either innate or acquired. MDR represents the end of the therapeutic pathway, and it practically leaves no treatment alternatives. Reversing MDR is an unfulfilled goal, despite the important recent advances in cancer research. MDR, the main cause of death in cancer patients, is a multi-factorial development, and most of its known causes have been thoroughly discussed in the literature. However, there is one aspect that has not received adequate consideration - intracellular alkalosis - which is part of wider pH deregulation where the pH gradient is inverted, meaning that extracellular pH is decreased and intracellular pH increased. This situation interacts with MDR and with the proteins involved, such as P-gp, breast cancer resistance protein, and multidrug associated resistance protein 1. However, there are also situations in which these proteins play no role at all, and where pH takes the lead. This is the case in ion trapping. Reversing the pH gradient to normal can be an important contribution to managing MDR. The drugs to manipulate pH exist, and most of them are FDA approved and in clinical use for other purposes. Furthermore, they have low or no toxicity and are inexpensive compared with any chemotherapeutic treatment. Repurposing these drugs and combining them in a reasonable fashion is one of the points proposed in this paper, which discusses the relationship between cancer’s peculiar pH and MDR.

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Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models

et al. 2021

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Triple negative breast cancers (TNBCs) are very aggressive and have a poor prognosis due to lack of efficacious therapies. The only effective treatment is chemotherapy that however is frequently hindered by the occurrence of drug resistance. We approached this problem in vitro and in vivo on a triple negative and a hormone sensitive breast cancer cell lines: 4T1 and TS/A. A main defense mechanism of tumors is the extrusion of intracellular protons derived from the metabolic shift to glycolysis, and necessary to maintain an intracellular pH compatible with life. The resulting acidic extracellular milieu bursts the malignant behavior of tumors and impairs chemotherapy. Therefore, we investigated the efficacy of combined therapies that associate cisplatin (Cis) with proton exchanger inhibitors, such as esomeprazole (ESO) and 5‐(N‐ethyl‐N‐isopropyl)amiloride (EIPA). Our results demonstrate that in the 4T1 triple negative model the combined therapy Cis plus EIPA is significantly more effective than the other treatments. Instead, in the TS/A tumor the best therapeutic result is obtained with ESO alone. Remarkably, in both 4T1 and TS/A tumors these treatments correlate with increase of CD8+ T lymphocytes and dendritic cells, and a dramatic reduction of M2 macrophages and other suppressor myeloid cells (MDSC) in the tumor infiltrates.

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Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models

Cited by 4 publications

References 51 publications

Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging—Chemical Exchange Saturation Transfer Tumor pH Imaging

Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging—Chemical Exchange Saturation Transfer Tumor pH Imaging

The complex relationship between multiple drug resistance and the tumor pH gradient: a review

Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models

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