Abstract
BackgroundMajor goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H + −rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma.MethodMG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin.ResultsPreclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients.ConclusionThis study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy.
Highlights
Low pH is a major cause of tumor unresponsiveness to the vast majority of cytotoxic drugs mostly due to the fact the H + −rich tumor microenvironment leads to protonation of the drug causing both its neutralization outside the cells and abrogation of drug entry within the target cell [1]
Preclinical experiments showed that pump inhibitors (PPI) sensitize both human osteosarcoma cell lines and xenografts to cisplatin
Preclinical data showing that pretreatment of drug-resistant tumor cells with proton pump inhibitors (PPI), renders tumor cells more sensitive to a variety of anticancer drugs [3] have suggested that the administration of PPI as chemosensitizers might be an innovative approach to increase the sensitivity of osteosarcoma cancer cells to the currently used drugs
Summary
Low pH is a major cause of tumor unresponsiveness to the vast majority of cytotoxic drugs mostly due to the fact the H + −rich tumor microenvironment leads to protonation of the drug causing both its neutralization outside the cells and abrogation of drug entry within the target cell [1]. Previous studies have shown that the preoperative chemotherapy dose-intensification [9] or the preoperative deliver of intra-arterial cisplatin [10,11] are able to increase the percentage of cases with a good response to neoadjuvant chemotherapy. Both strategies are associated with more severe side effects and discomfort for the patient [9,11]. An in vivo study performed in companion animals with spontaneous occurring tumors, including osteosarcoma, has shown an amazing clinical response to high dosage PPI/chemotherapy combination [12]. We investigated the effects of PPI in chemosensitizing osteosarcoma
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