Synergistic increase in efficacy of a combination of 2-deoxy-D-glucose and cisplatin in normoxia and hypoxia: switch from autophagy to apoptosis.
Resistance to drugs, which is aggravated by hypoxia, is a well-known feature of tumors. The combination of drug exposure and hypoxia can give rise to several survival strategies in the exposed cells. Glioblastoma multiforme (GBM) is among the most hypoxic of solid tumors, and we have used glial cells to identify a drug combination that would be synergistically effective in these cells under both normoxia and hypoxia. Cisplatin (CP) and 2-deoxy-D-glucose (2-DG), which have been used for second-line therapy and for preclinical research, are relatively ineffective as single agents. During in vitro experiments with A172 and LN229 cells, there was increased resistance to both drugs under hypoxia. However, the combination of CP and 2-DG showed a synergistic effect in reducing cell viability under both normoxia and hypoxia, with a combination index of less than 1. Increased autophagy is a distinct feature of the response to 2-DG. However, autophagic markers were reduced, and apoptotic markers were upregulated by the combination, indicating a switch over from autophagic to apoptotic pathways with reduction in endoplasmic reticulum (ER) stress. The combination also resulted in a decrease of pAKT levels. The effect of CP in the combination was replicated by the prototype AKT inhibitor LY294002, further supporting the role of AKT inhibition in the synergism. Combination of 2-DG with CP, or possibly an AKT inhibitor, can prove to be an effective rational combination for reducing chemoresistance under both normoxic and hypoxic conditions in gliomas.
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India.|Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India.
Akansha
A
Jalota
National Brain Research Centre, Manesar, Gurgaon, 122051, India.
Mukesh
M
Kumar
Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India.|Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, 201313, India.
Bhudev C
BC
Das
Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India.
Ajay K
AK
Yadav
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India.
Kunzang
K
Chosdol
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India. sub_sinha@hotmail.com.|National Brain Research Centre, Manesar, Gurgaon, 122051, India. sub_sinha@hotmail.com.
Subrata
S
Sinha
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D015870:Gene Expression / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D002867:Chromones; D009025:Morpholines; D051028:bcl-2-Associated X Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003606:Dacarbazine; D003847:Deoxyglucose; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin; D010100:Oxygen; D000077204:Temozolomide
Chemosensitization; Combinatorial therapy; Glioma