Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer

Abstract

The multi-target kinase inhibitor sorafenib has been approved for the treatment of patients with advanced differentiated thyroid cancer. However, different sensitivities to sorafenib have been observed, and few patients have benefited from sorafenib treatment in the long term. In the event of acquired resistance to sorafenib it is not beneficial to continue treatment in most patients. Autophagy can be induced in a variety of cancer treatments and plays an important role in cancer treatment. The role of autophagy in sorafenib treatment of thyroid cancer has not been fully demonstrated. The present study investigated whether autophagy is activated by sorafenib during the treatment of thyroid cancer, examined the underlying mechanisms, and explored potential strategies to enhance the therapeutic sensitivity of sorafenib. Chloroquine (CQ) is an autophagy inhibitor that has been reported to increase sensitivity to various cancer treatments. Thyroid cancer xenograft model mice were treated with sorafenib, CQ, or a combination of sorafenib and CQ. We observed that CQ or sorafenib treatment suppressed tumor growth, while mice treated with the combination of sorafenib and CQ displayed significantly reduced tumor growth compared with those treated with sorafenib or CQ alone. Western blotting results indicated that sorafenib concurrently inhibited the activities of the MAPK and AKT/mTOR pathways in thyroid cancer. Autophagy was activated by sorafenib in thyroid cancer, both in vitro and in vivo, which was at least in part due to suppression of the AKT/mTOR pathway. Combination treatment including CQ could inhibit the autophagic flux induced by sorafenib. Silencing the key autophagy gene ATG5 using small interfering RNA also increased the anticancer effect of sorafenib. In summary, the present study revealed that inhibition of autophagy enhances the anticancer effect of sorafenib, and the combination of CQ with sorafenib treatment represents a potential therapeutic strategy for treating advanced differentiated thyroid cancer.

Long Term Pharmacological Perturbation of Autophagy in Mice: Are HCQ Injections a Relevant Choice?

“…Of note, we used HCQ at doses similar to what has been reported in the literature, ranging from 10 to 80 mg/kg, that are relevant to human curative treatment but with a lower frequency of injection. Indeed, short term rodent studies generally use a daily injection of pharmacological treatment [45,48,50,[79][80][81][82][83] but this daily schedule is inappropriate for long term studies. Therefore, instead of basing the injection schedule on curative HCQ treatment, we based the schedule on the prophylactic HCQ treatment in humans which recommends weekly injections of the pharmacological agent [84].…”

Combinatorial Therapies in Thyroid Cancer: An Overview of Preclinical and Clinical Progresses

“…This has been tested in vivo and has shown improved efficacy of sorafenib in treating thyroid cancer xenograft mice. However, due the complexity of the mechanism induced by the combination, it is difficult to clearly established if the two molecules acted in additivity or synergy [86].…”

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

“…Strategies based on the blockage of autophagy usually combine traditional inhibitors with cancer therapies. As an example, the use of chloroquine (CQ) during Sorafenib treatment in a thyroid cancer subcutaneous mice model, markedly reduced tumor volume and enhanced caspase-3 activation [75]. In HCC, combination of the PARP inhibitor Niraparib and CQ increased cell death and DNA damage [76].…”