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Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition.

Abstract Osteosarcoma is the most frequent primary malignant bone tumor. Although survival has distinctly increased due to neoadjuvant chemotherapy in the past, patients with metastatic disease and poor response to chemotherapy still have an adverse prognosis. Hence, development of new therapeutic strategies is still of utmost importance.
PMID
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Authors

Mayor MeshTerms
Keywords

Anticancer gallium compound

Autophagy

KP46

Obatoclax

Osteosarcoma

Journal Title journal of experimental & clinical cancer research : cr
Publication Year Start




PMID- 28403890
OWN - NLM
STAT- MEDLINE
DA  - 20170413
DCOM- 20170414
LR  - 20170416
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Linking)
VI  - 36
IP  - 1
DP  - 2017 Apr 12
TI  - Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma
      cells - synergism with autophagy inhibition.
PG  - 52
LID - 10.1186/s13046-017-0527-z [doi]
AB  - BACKGROUND: Osteosarcoma is the most frequent primary malignant bone tumor.
      Although survival has distinctly increased due to neoadjuvant chemotherapy in the
      past, patients with metastatic disease and poor response to chemotherapy still
      have an adverse prognosis. Hence, development of new therapeutic strategies is
      still of utmost importance. METHODS: Anticancer activity of KP46 against
      osteosarcoma cell models was evaluated as single agent and in combination
      approaches with chemotherapeutics and Bcl-2 inhibitors using MTT assay.
      Underlying mechanisms were tested by cell cycle, apoptosis and autophagy assays. 
      RESULTS: KP46 exerted exceptional anticancer activity at the nanomolar to low
      micromolar range, depending on the assay format, against all osteosarcoma cell
      models with minor but significant differences in IC50 values. KP46 treatment of
      osteosarcoma cells caused rapid loss of cell adhesion, weak cell cycle
      accumulation in S-phase and later signs of apoptotic cell death. Furthermore,
      already at sub-cytotoxic concentrations KP46 reduced the migratory potential of
      osteosarcoma cells and exerted synergistic effects with cisplatin, a standard
      osteosarcoma chemotherapeutic. Moreover, the gallium compound induced signs of
      autophagy in osteosarcoma cells. Accordingly, blockade of autophagy by
      chloroquine but also by the Bcl-2 inhibitor obatoclax increased the cytotoxic
      activity of KP46 treatment significantly, suggesting autophagy induction as a
      protective mechanism against KP46. CONCLUSION: Together, our results identify
      KP46 as a new promising agent to supplement standard chemotherapy and possible
      future targeted therapy in osteosarcoma.
FAU - Kubista, Bernd
AU  - Kubista B
AD  - Department of Orthopedics, Medical University of Vienna, Waehringerguertel 18-20,
      A-1090, Vienna, Austria.
FAU - Schoefl, Thomas
AU  - Schoefl T
AD  - Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer
      Center, Medical University Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.
FAU - Mayr, Lisa
AU  - Mayr L
AD  - Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer
      Center, Medical University Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.
FAU - van Schoonhoven, Sushilla
AU  - van Schoonhoven S
AD  - Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer
      Center, Medical University Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.
FAU - Heffeter, Petra
AU  - Heffeter P
AD  - Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer
      Center, Medical University Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.
AD  - Research Platform "Translational Cancer Therapy Research", University Vienna and 
      Medical University Vienna, Vienna, Austria.
FAU - Windhager, Reinhard
AU  - Windhager R
AD  - Department of Orthopedics, Medical University of Vienna, Waehringerguertel 18-20,
      A-1090, Vienna, Austria.
FAU - Keppler, Bernhard K
AU  - Keppler BK
AD  - Research Platform "Translational Cancer Therapy Research", University Vienna and 
      Medical University Vienna, Vienna, Austria.
AD  - Institute of Inorganic Chemistry, University of Vienna, Waehringerstr. 42,
      A-1090, Vienna, Austria.
FAU - Berger, Walter
AU  - Berger W
AD  - Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer
      Center, Medical University Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.
      [email protected]
AD  - Research Platform "Translational Cancer Therapy Research", University Vienna and 
      Medical University Vienna, Vienna, Austria. [email protected]
LA  - eng
PT  - Journal Article
DEP - 20170412
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - 0 (Organometallic Compounds)
RN  - 0 (Pyrroles)
RN  - 0 (obatoclax)
RN  - 0 (tris(8-quinolinolato)gallium (III))
RN  - 5UTX5635HP (Oxyquinoline)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Autophagy/drug effects
MH  - Bone Neoplasms/*drug therapy/pathology
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Drug Screening Assays, Antitumor
MH  - Drug Synergism
MH  - Humans
MH  - Molecular Targeted Therapy
MH  - Organometallic Compounds/administration & dosage/*pharmacology
MH  - Osteosarcoma/*drug therapy/pathology
MH  - Oxyquinoline/administration & dosage/*analogs & derivatives/pharmacology
MH  - Pyrroles/administration & dosage
PMC - PMC5389188
OTO - NOTNLM
OT  - Anticancer gallium compound
OT  - Autophagy
OT  - KP46
OT  - Obatoclax
OT  - Osteosarcoma
EDAT- 2017/04/14 06:00
MHDA- 2017/04/15 06:00
CRDT- 2017/04/14 06:00
PHST- 2017/01/01 [received]
PHST- 2017/04/05 [accepted]
AID - 10.1186/s13046-017-0527-z [doi]
AID - 10.1186/s13046-017-0527-z [pii]
PST - epublish
SO  - J Exp Clin Cancer Res. 2017 Apr 12;36(1):52. doi: 10.1186/s13046-017-0527-z.

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