A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

Abstract

Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L). L is used in psychiatric practice, yet also bears anti-diabetic potential and selectively inhibits glycogen synthase kinase-3 beta (GSK-3β). M, a biguanide class anti-diabetic agent shows anticancer activity via activating AMP-activated protein kinase (AMPK). Glitazones bind to PPAR-γ and inhibit NF-κB, triggering cell proliferation, apoptosis resistance and synthesis of inflammatory cytokines in cancer cells. Inhibition of inflammatory cytokines could simultaneously decrease tumor growth and alleviate cancer cachexia, having a major role in PC mortality. Furthermore, mutual synergistic interactions exist between PPAR-γ and GSK-3β, between AMPK and GSK-3β and between AMPK and PPAR-γ. In GBM, M blocks angiogenesis and migration in experimental models. Very noteworthy, among GBM patients with type 2 diabetes, usage of M significantly correlates with better survival while reverse is true for sulfonylureas. In experimental models, P synergies with ligands of RAR, RXR and statins in reducing growth of GBM. Further, usage of P was found to be lesser in anaplastic astrocytoma and GBM patients, indicating a protective effect of P against high-grade gliomas. L is accumulated in GBM cells faster and higher than in neuroblastoma cells, and its levels further increase with chronic exposure. Recent studies revealed anti-invasive potential of L in GBM cell lines. Here, we propose that a triple-agent regime including drugs already in clinical usage may provide a metabolic adjuvant therapy for PC and GBM.

ZIP4 Promotes Muscle Wasting and Cachexia in Mice With Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells

“…40,41 Very few studies have been done to investigate the impact of adjuvant therapy and surgery on cancer cachexia and muscle wasting in pancreatic cancer. 42,43 In this study, we found that tumor removal plus ZIP4 knockdown stabilized body weight. Specifically, knockdown of ZIP4 in pancreatic cancer cells ameliorated muscle wasting in mice, as indicated by higher muscle mass, decreased protein degradation, and preserved myofiber cross-sectional area.…”

Caffeic Acid Expands Anti-Tumor Effect of Metformin in Human Metastatic Cervical Carcinoma HTB-34 Cells: Implications of AMPK Activation and Impairment of Fatty Acids De Novo Biosynthesis

“…Therefore, the objective of the novel approach is to develop molecularly targeted anticancer strategies combining specific activities of anticancer compounds in order to improve the outcome of the treatment [3,16,17]. Recent findings suggest that combined therapy may be efficient to increase tumor regression, to prolong the remission of cancer, and to prevent metastasis.…”

Impact of Fetuin-A (AHSG) on Tumor Progression and Type 2 Diabetes

“…Other investigators have also reported the ectopic synthesis of fetuin-A by pancreatic cancer cells [54,55] and prostate cancer cells [45]. Interestingly, the tumors cells in which ectopic synthesis of fetuin-A has been determined, namely glioblastoma and pancreatic cancer, also happen to be some of the most invasive tumor types [56], suggesting that the glycoprotein plays a significant and yet to be fully appreciated role in tumor progression. For example, the ectopic fetuin-A may promote angiogenesis, particularly in glioblastomas that have elaborate blood supply lines [26].…”