Gemcitabine and Rapamycin Exhibit Additive Effect against Osteosarcoma by Targeting Autophagy and Apoptosis
by
Takashi Ando
*, 
Jiro Ichikawa
,
Taro Fujimaki
,
Naofumi Taniguchi
,
Yoshihiro Takayama
and
Hirotaka Haro
Department of Orthopeadic Surgery, Yamanashi University School of Medicine, Yamanashi 409-3898, Japan
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(11), 3097; https://doi.org/10.3390/cancers12113097
Submission received: 7 September 2020
/
Revised: 12 October 2020
/
Accepted: 21 October 2020
/
Published: 23 October 2020
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
Simple Summary
Osteosarcoma is the most common solid cancer of the bone. Unfortunately, the expected outcome for patients with this and similar types of cancers has changed little over the last 20 years. One important need is to develop new therapies that overcome the development of drug resistance in osteosarcoma cells. The drug gemcitabine (Gem) can kill osteosarcoma cells and prevent them from growing and spreading. Another drug, rapamycin (Rapa), can also kill osteosarcoma cells, but does so in a different way. Here, we investigated whether a combination of Rapa and Gem would exhibit better osteosarcoma treatment efficiency than Rapa and Gem monotherapies. We found that this drug combination was very effective at killing osteosarcoma cells, both in cell cultures and in mice, and the combinatorial treatment was better than treatment with a single agent. Therefore, combinatorial therapy with Gem and Rapa may be an effective approach for treating drug resistant osteosarcoma cells.
Abstract
The overall prognosis for sarcoma-based cancer patients has remained largely unchanged over the past 10 years. Because there is no effective anticancer drug for patients with chemoresistant osteosarcoma (OS), novel approaches are needed to improve the prognosis. Here, we investigated whether rapamycin (Rapa) could enhance the anti-tumor effects of gemcitabine (Gem) in OS. Gem dose-dependently killed the OS cells, but exhibited much lower cytotoxicity on osteoblasts. Treatment with a combination Gem and Rapa was much more effective than that of either single agent with respect to reducing cell viability, cell invasion, cell migration, and vascular endothelial growth factor production in vitro. Moreover, the combination of these agents suppressed tumor growth, angiogenesis, and lung metastasis in allograft and xenograft murine models of OS with minimal adverse effects. Overall, the combination therapy prolonged the overall survival of tumor-bearing mice. Mechanistically, Gem induced apoptosis and increased the levels of cleaved caspases, while Rapa induced autophagy and microtubule-associated protein light chain 3 (LC3)-I/LC3-II expression both in vitro and in vivo. Our findings suggest that chemotherapy using Gem combined with Rapa may be a novel and promising therapeutic approach for the treatment of OS.
Keywords:
gemcitabine; rapamycin; autophagy; apoptosis; angiogenesis
