Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth

Yong Zhao, Mei Juan Tu, Yi Feng Yu, Wei Peng Wang, Qiu Xia Chen, Jing Xin Qiu, Ai Xi Yu, Aiming Yu

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent.

Original languageEnglish (US)
Pages (from-to)602-613
Number of pages12
JournalBiochemical Pharmacology
Volume98
Issue number4
DOIs
StatePublished - Dec 15 2015

Fingerprint

Prodrugs
Osteosarcoma
MicroRNAs
Doxorubicin
Growth
Therapeutics
Tumors
Heterografts
G2 Phase Cell Cycle Checkpoints
Bioengineering
Chemotherapy
Proto-Oncogenes
Cell proliferation
Cell growth
Intercalation
RNA Interference
Combination Drug Therapy
Young Adult
Bone
Blood

Keywords

  • Chemotherapy
  • Doxorubicin
  • miR-34a
  • Orthotopic tumor
  • Osteosarcoma

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth. / Zhao, Yong; Tu, Mei Juan; Yu, Yi Feng; Wang, Wei Peng; Chen, Qiu Xia; Qiu, Jing Xin; Yu, Ai Xi; Yu, Aiming.

In: Biochemical Pharmacology, Vol. 98, No. 4, 15.12.2015, p. 602-613.

Research output: Contribution to journalArticle

Zhao, Yong ; Tu, Mei Juan ; Yu, Yi Feng ; Wang, Wei Peng ; Chen, Qiu Xia ; Qiu, Jing Xin ; Yu, Ai Xi ; Yu, Aiming. / Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth. In: Biochemical Pharmacology. 2015 ; Vol. 98, No. 4. pp. 602-613.
@article{22a9da5efec7480f96b2a3afb25898a9,
title = "Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth",
abstract = "Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent.",
keywords = "Chemotherapy, Doxorubicin, miR-34a, Orthotopic tumor, Osteosarcoma",
author = "Yong Zhao and Tu, {Mei Juan} and Yu, {Yi Feng} and Wang, {Wei Peng} and Chen, {Qiu Xia} and Qiu, {Jing Xin} and Yu, {Ai Xi} and Aiming Yu",
year = "2015",
month = "12",
day = "15",
doi = "10.1016/j.bcp.2015.10.015",
language = "English (US)",
volume = "98",
pages = "602--613",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth

AU - Zhao, Yong

AU - Tu, Mei Juan

AU - Yu, Yi Feng

AU - Wang, Wei Peng

AU - Chen, Qiu Xia

AU - Qiu, Jing Xin

AU - Yu, Ai Xi

AU - Yu, Aiming

PY - 2015/12/15

Y1 - 2015/12/15

N2 - Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent.

AB - Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent.

KW - Chemotherapy

KW - Doxorubicin

KW - miR-34a

KW - Orthotopic tumor

KW - Osteosarcoma

UR - http://www.scopus.com/inward/record.url?scp=84947223452&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84947223452&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2015.10.015

DO - 10.1016/j.bcp.2015.10.015

M3 - Article

VL - 98

SP - 602

EP - 613

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 4

ER -