br n Catholic Fu Jen University Hospital
n Catholic Fu Jen University Hospital, New Taipei City, Taiwan
o Naxospharma, Via Giuseppe di Vittorio 70, Novate Milanese, 20026, Italy
Signal transduction inhibitors
Pancreatic cancer is devastating cancer worldwide with few if any truly eﬀective therapies. Pancreatic cancer has an increasing incidence and may become the second leading cause of death from cancer. Novel, more eﬀective therapeutic approaches are needed as pancreatic cancer pa-tients usually survive for less than a year after being diagnosed. Control of blood sugar levels by the prescription drug metformin in diseases such as MPP+ Iodide has been examined in as-sociation with pancreatic cancer. While the clinical trials remain inconclusive, there is hope that certain diets and medications may aﬀect positively the outcomes of patients with pancreatic and other cancers. Other natural compounds may share some of the eﬀects of metformin. One “medicinal” fruit consumed by millions worldwide is berberine (BBR). Metformin and BBR both activate AMP-activated protein kinase (AMPK) which is a key mediator of glucose metabolism.
∗ Corresponding author. ∗∗ Corresponding author. E-mail addresses: [email protected] (S.M. Akula), [email protected] (J.A. McCubrey). 1 Co-first authors: Shaw M. Akula and Saverio Candido. These authors contributed equally to these studies.
S.M. Akula, et al. Advances in Biological Regulation xxx (xxxx) xxxx
Glucose metabolism has been shown to be very important in cancer and its significance is in-creasing. In the following studies, we have examined the eﬀects of metformin, BBR and a panel of modified BBRs (NAX compounds) and chemotherapeutic drugs on the growth of four diﬀerent human pancreatic adenocarcinoma cell lines (PDAC). Interestingly, the eﬀects of metformin could be enhanced by BBR and certain modified BBRs. Upon restoration of WT-TP53 activity in MIA-PaCa-2 cells, an altered sensitivity to the combination of certain NAX compounds and metformin was observed compared to the parental cells which normally lack WT-TP53. Certain NAX compounds may interact with WT-TP53 and metformin treatment to alter the expression of key molecules involved in cell growth. These results suggest a therapeutic approach by com-bining certain pharmaceutical drugs and nutraceuticals to suppress the growth of cancer cells.
Previously, we have summarized many of the key genetic and biological factors implicated in pancreatic cancer (Candido et al., 2018; Abrams et al., 2018, 2019; McCubrey et al., 2018). Although various genetics and environmental factors may be involved in pancreatic cancer, few remedies have been developed to treat this devastating disease beyond surgery and chemotherapy which, unfortunately, only have minimal positive eﬀects on patient survival. Clearly novel, more eﬀective approaches are needed to treat pancreatic ductal adenocarcinoma (PDAC) and the subsequent drug resistance which may arise.
Metformin (N,N-dimethylimidodicarbonimidic diamide) is a type II diabetes drug which also has eﬀects on cancer (Lonardo et al., 2013; Candido et al., 2018). Metformin mainly blocks hepatic gluconeogenesis. Cancer cells normally have high glucose requirements due to their frequent utilization of the ineﬃcient breakdown of glucose by the anerobic pyruvate pathway (Warburg eﬀect) to generate ATP. Thus, metformin can have anti-cancer eﬀects by modulation of glucose and energy levels in cancer cells. Epidemio-logical studies have suggested that metformin may have eﬀects on PDAC development.
However, the relationship between metformin use and PDAC development and survival remains controversial (Bosetti et al., 2014). While some studies suggested a benefit for PDAC patients who consumed metformin (Cerullo et al., 2017) other investigations