Metabolic interrogation as a tool to optimize chemotherapeutic regimens
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Vlad C. Sandulache1,2,*, Yunyun Chen1,*, Lei Feng3, William N. William4, Heath D. Skinner5, Jeffrey N. Myers1, Raymond E. Meyn6, Jinzhong Li1,7, Ainiwaer Mijiti1,8, James A. Bankson9, Clifton D. Fuller5, Marina Y. Konopleva10, Stephen Y. Lai1,11
1Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA
3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
5Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
6Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
7Department of Oral and Maxillofacial-Head and Neck Surgery, Beijing Stomatological Hospital, Beijing, China
8Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
9Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
10Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
11Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
*These authors have contributed equally to this work
Stephen Y. Lai, email: firstname.lastname@example.org
Keywords: cisplatin, p53, lactate, head and neck squamous cell carcinoma, acute myelogenous leukemia
Received: August 17, 2016 Accepted: December 31, 2016 Published: February 08, 2017
Platinum-based (Pt) chemotherapy is broadly utilized in the treatment of cancer. Development of more effective, personalized treatment strategies require identification of novel biomarkers of treatment response. Since Pt compounds are inactivated through cellular metabolic activity, we hypothesized that metabolic interrogation can predict the effectiveness of Pt chemotherapy in a pre-clinical model of head and neck squamous cell carcinoma (HNSCC).
We tested the effects of cisplatin (CDDP) and carboplatin (CBP) on DNA damage, activation of cellular death cascades and tumor cell metabolism, specifically lactate production. Pt compounds induced an acute dose-dependent, transient drop in lactate generation in vitro, which correlated with effects on DNA damage and cell death. Neutralization of free radical stress abrogated these effects. The magnitude of this effect on lactate production correlated with the differential sensitivity of HNSCC cells to Pt compounds (CDDP vs CBP) and p53-driven Pt chemotherapy resistance. Using dual flank xenograft tumors, we demonstrated that Pt-driven effects on lactate levels correlate with effects on tumor growth delay in a dose-dependent manner and that lactate levels can define the temporal profile of Pt chemotherapy-induced metabolic stress. Lactate interrogation also predicted doxorubicin effects on cell death in both solid tumor (HNSCC) and acute myelogenous leukemia (AML) cell lines.
Real-time metabolic interrogation of acute changes in cell and tumor lactate levels reflects chemotherapy effects on DNA damage, cell death and tumor growth delay. We have identified a real-time biomarker of chemotherapy effectiveness which can be used to develop adaptive, iterative and personalized treatment regimens against a variety of solid and hematopoietic malignancies.
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