The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy

Abstract

Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone. As add-on to current standard treatment with capecitabine, ABC7 uses ancillary attributes of seven already-marketed noncancer treatment drugs to stop both the natural EMT process inherent to breast cancer and the added EMT occurring as a response to current treatment modalities. Chemotherapy, radiation, and surgery provoke EMT in cancer generally and in breast cancer specifically. ABC7 uses standard doses of capecitabine as used in treating breast cancer today. In addition, ABC7 uses 1) an older psychiatric drug, quetiapine, to block RANK signaling; 2) pirfenidone, an anti-fibrosis drug to block TGF-beta signaling; 3) rifabutin, an antibiotic to block beta-catenin signaling; 4) metformin, a first-line antidiabetic drug to stimulate AMPK and inhibit mammalian target of rapamycin, (mTOR); 5) propranolol, a beta-blocker to block beta-adrenergic signaling; 6) agomelatine, a melatonergic antidepressant to stimulate M1 and M2 melatonergic receptors; and 7) ribavirin, an antiviral drug to prevent eIF4E phosphorylation. All these block the signaling pathways – RANK, TGF-beta, mTOR, beta-adrenergic receptors, and phosphorylated eIF4E – that have been shown to trigger EMT and enhance breast cancer growth and so are worthwhile targets to inhibit. Agonism at MT1 and MT2 melatonergic receptors has been shown to inhibit both breast cancer EMT and growth. This ensemble was designed to be safe and augment capecitabine efficacy. Given the expected outcome of metastatic breast cancer as it stands today, ABC7 warrants a cautious trial.

Long non-coding (lnc)RNA profiling and the role of a key regulator lnc-PNRC2-1 in the transforming growth factor-β1-induced epithelial–mesenchymal transition of CNE1 nasopharyngeal carcinoma cells

“…Among them, HSD11B1-AS1 (lnc-LAMB3-1), AC008695.1, and MAGEC2 have been reported to be key for tumor cell EMT. 33–35 We found that the extent of EMT was significantly reduced after treatment with a TGF-β1 inhibitor, as shown by significant changes in the expression of EMT marker proteins. Taken together, these findings revealed that expression changes of lncRNAs are closely related to the occurrence and development of EMT in CNE1 cells.…”

Antitumor effects of ribavirin in combination with TMZ and IFN‑β in malignant glioma cells

“…Although the mechanism underlying the anti-viral and anti-tumor effects of ribavirin has not yet been fully elucidated, several participating/possible processes have been mentioned above. Kast et al (28) pointed out the following major mechanisms of action, particularly related to the anti-viral action: i) actual intermingling within the viral RNA; ribavirin enters the cell via a nucleoside transport mechanism, subsequently inhibiting/altering viral RNA synthesis, ii) structural analogy to GTP; incorporation into the cell passively, then binding/inhibiting RNA polymerase/RNA synthesis, iii) immune clearance; immune-stimulation by up-regulation of cytokines to shift the Th1/2 cell balance to Th1 dominance, iv) inhibition of eIF4E; thereby inhibiting mRNA capping and translation initiation, v) modulation of IFN-related gene expression, vi) inhibition of IMPDH; with consequent depletion of intracellular GTP, and vii) RNA mutagen; following triphosphorylation, ribavirin triphosphate is incorporated into replicating RNA viral RNA polymerases with consequent induction of viral mutagenesis. These processes are attractive as factors in the repurposing of the anti-viral ribavirin as an anti-tumor agent, and also in the mechanism underlying the synergistic effect of ribavirin in combination with other agents.…”

The Use of Ribavirin as an Anticancer Therapeutic: Will It Go Viral?

“…Mechanistically, this same study found that in addition to inhibition of eIF4E, there was significant reduction in the activity of matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-9 (MMP-9). These proteins are integral to mesenchymal cancer cell invasion and epithelial-tomesenchymal transition (EMT) for metastasis, and these findings have led to proposed treatment schemas for using ribavirin in combination with other agents that target distinct pathways involved in EMT (23,24). This has resulted in phase I/II clinical trials assessing the efficacy of ribavirin in metastatic breast cancer and other solid tumors, the results of which have yet to be reported (NCT01056757 and NCT01309490).…”