Combined therapy of oncolytic adenovirus and temozolomide enhances lung cancer virotherapy in vitro and in vivo

Jorge G Gomez-Gutierrez; Jonathan Nitz; Rajesh Sharma; Stephen L Wechman; Eric Riedinger; Elvis Martinez-Jaramillo; Heshan Sam Zhou; Kelly M McMasters

doi:10.1016/j.virol.2015.10.019

Combined therapy of oncolytic adenovirus and temozolomide enhances lung cancer virotherapy in vitro and in vivo

Virology. 2016 Jan:487:249-59. doi: 10.1016/j.virol.2015.10.019. Epub 2015 Nov 9.

Authors

Jorge G Gomez-Gutierrez¹, Jonathan Nitz², Rajesh Sharma³, Stephen L Wechman², Eric Riedinger², Elvis Martinez-Jaramillo², Heshan Sam Zhou⁴, Kelly M McMasters⁴

Affiliations

¹ Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: jgguti01@louisville.edu.
² Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.
³ Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
⁴ Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.

Abstract

Oncolytic adenoviruses (OAds) are very promising for the treatment of lung cancer. However, OAd-based monotherapeutics have not been effective during clinical trials. Therefore, the effectiveness of virotherapy must be enhanced by combining OAds with other therapies. In this study, the therapeutic potential of OAd in combination with temozolomide (TMZ) was evaluated in lung cancer cells in vitro and in vivo. The combination of OAd and TMZ therapy synergistically enhanced cancer cell death; this enhanced cancer cell death may be explained via three related mechanisms: apoptosis, virus replication, and autophagy. Autophagy inhibition partially protected cancer cells from this combined therapy. This combination significantly suppressed the growth of subcutaneous H441 lung cancer xenograft tumors in athymic nude mice. In this study, we have provided an experimental rationale to test OAds in combination with TMZ in a lung cancer clinical trial.

Keywords: Adenovirus; Apoptosis; Autophagy; Cancer; Lung; Oncolytic; Temozolomide.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenoviridae / physiology
Adenoviridae Infections / virology
Adenovirus E1B Proteins / genetics
Animals
Antineoplastic Agents, Alkylating / therapeutic use*
Apoptosis / drug effects*
Autophagy / drug effects
Cell Line, Tumor
Combined Modality Therapy / methods
DNA Modification Methylases / metabolism
DNA Repair Enzymes / metabolism
Dacarbazine / analogs & derivatives*
Dacarbazine / therapeutic use
HEK293 Cells
Humans
JNK Mitogen-Activated Protein Kinases / genetics
Lung Neoplasms / therapy*
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Oncolytic Virotherapy / methods*
Oncolytic Viruses / physiology
Temozolomide
Tumor Suppressor Proteins / metabolism
Virus Replication
Xenograft Model Antitumor Assays / methods

Substances

Adenovirus E1B Proteins
Antineoplastic Agents, Alkylating
Tumor Suppressor Proteins
Dacarbazine
DNA Modification Methylases
MGMT protein, human
JNK Mitogen-Activated Protein Kinases
DNA Repair Enzymes
Temozolomide

Abstract

Publication types

MeSH terms

Substances

Grants and funding