Prevention of multidrug resistance (MDR) in osteosarcoma by NSC23925.
BACKGROUND
The major limitation to the success of chemotherapy in osteosarcoma is the development of multidrug resistance (MDR). Preventing the emergence of MDR during chemotherapy treatment has been a high priority of clinical and investigational oncology, but it remains an elusive goal. The NSC23925 has recently been identified as a novel and potent MDR reversal agent. However, whether NSC23925 can prevent the development of MDR in cancer is unknown. Therefore, this study aims to evaluate the effects of NSC23925 on prevention of the development of MDR in osteosarcoma.


METHODS
Human osteosarcoma cell lines U-2OS and Saos were exposed to increasing concentrations of paclitaxel alone or in combination with NSC23925 for 6 months. Cell sublines selected at different time points were evaluated for their drug sensitivity, drug transporter P-glycoprotein (Pgp) expression and activity.


RESULTS
We observed that tumour cells selected with increasing concentrations of paclitaxel alone developed MDR with resistance to paclitaxel and other Pgp substrates, whereas cells cultured with paclitaxel-NSC23925 did not develop MDR and cells remained sensitive to chemotherapeutic agents. Paclitaxel-resistant cells showed high expression and activity of the Pgp, whereas paclitaxel-NSC23925-treated cells did not express Pgp. No changes in IC50 and Pgp expression and activity were observed in cells grown with the NSC23925 alone.


CONCLUSIONS
Our findings suggest that NSC23925 may prevent the development of MDR by specifically preventing the overexpression of Pgp. Given the significant incidence of MDR in osteosarcoma and the lack of effective agents for prevention of MDR, NSC23925 and derivatives hold the potential to improve the outcome of cancer patients with poor prognosis due to drug resistance.
1] Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA [2] Department of Gynaecology and Obstetrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
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Yang
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA.
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P
Yang
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA.
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J
Shen
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA.
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E
Osaka
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA.
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E
Choy
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA.
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G
Cote
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA.
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D
Harmon
Department of Gynaecology and Obstetrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
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Zhang
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA.
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H
Mankin
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA.
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FJ
Hornicek
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Jackson 1115, Boston, MA 02114, USA.
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Z
Duan
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*
C546115:(2-(4-methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D010880:Piperidines; D011804:Quinolines; D017239:Paclitaxel