Metformin-panobinostat combination against bladder cancer: National Defense Medical College scientists found a new way to overcome histone deacetylase inhibitor-caused mTOR activation

Bladder cancer is said to be the second most common malignancy of the genitourinary tract with significant morbidity and mortality. There is no curative treatment for patients with advanced form of this disease. Current treatment regimen includes cisplatin-based combinations which are used for treating patients with metastatic bladder cancer but their efficacy is limited. Other immunotherapeutic agents which target programmed cell death protein 1 and programmed death-ligand only prolong overall survival by several months. This has created a need for further research into new treatment strategies for advanced bladder cancer.

To this effect, National Defense Medical College scientists led by Dr. Akinori Sato reported the killing activity and combined effect of a histone deacetylase inhibitor, panobinostat and an antidiabetic drug, metformin on the growth of bladder cancer cells both in in vitro and in animal disease models. The work of the research team comprised also of Dr. Kazuki Okubo, Dr. Makoto Isono, and Ms. Takako Asano is now published in the peer-reviewed journal, Translational oncology.

The research team observed that panobinostat inhibited the growth of bladder cancer cells and induced histone acetylation in a dose-dependent manner. They also looked thoroughly at the mechanism of how panobinostat interact with bladder cancer cells and found that the drug induces endoplasmic reticulum (ER) stress evidenced by the increased expression of glucose-regulated protein 78 and endoplasmic reticulum resident protein 44. Moreover, panobinostat decreased the expression of phosphorylated 4E-binding protein 1 (4EBP1), showing that it inhibited one of the downstream proteins of the mammalian target of rapamycin (mTOR) pathway. However, panobinostat increased the phosphorylation of ribosomal protein S6 (S6), a downstream protein of the mTOR pathway located at a different signaling axis from 4EBP1, showing that the anticancer activity of panobinostat alone is reduced because despite its suppression of one signaling aspect of the mTOR pathway it activates another signaling pathway.

Dr. Akinori Sato and his colleagues also investigated the amplifying effect of the popular antidiabetic drug metformin on panobinostat’s antineoplastic activity in bladder cancer cells. Metformin inhibits the mTOR pathway by activating AMP-activated protein kinase (AMPK), an energy sensor in the cell. They thought that metformin would enhance panobinostat’s anticancer activity by suppressing panobinostat-induced mTOR activation.

The combination of panobinostat and metformin inhibited the growth of bladder cancer cells effectively in vitro as well as in vivo. Synergism of the combination was also confirmed by isobologram analysis as well as calculation of combination index. Mechanistically, metformin activated AMPK and inhibited panobinostat-caused phosphorylation of S6, thus inhibiting the activation of the mTOR pathway by panobinostat. Furthermore, they found that the AMPK activation by metformin enhanced panobinostat-induced histone acetylation synergistically by decreasing the expression of acetyl CoA carboxylase.

To confirm even further the benefit of a combined effect of a histone deacetylase inhibitor like panobinostat and metformin, the Japanese researchers treated the bladder cancer cells with other histone deacetylase inhibitors; suberoylanilide hydroxamic acid and entinostat. In combination with metformin they were found to also inhibit bladder cancer growth synergistically. They also reported the two drug combination is safe with no significant treatment-associated adverse events.

The study by National Defense Medical College researchers is actually is the first of its kind to investigate the interaction of panobinostat and metformin in cancer cells. Furthermore, the current study is noteworthy in terms of drug repositioning, i.e., combining drugs already used for other purposes aiming to reduce cost and time to develop new anticancer drugs. Results from the study may provide the basis for future testing and clinical trials in patients with advanced bladder cancer.