Ranolazine

Ranolazine: a potential anti-metastatic drug targeting voltage-gated sodium channels

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Abstract

Background

Multi-faceted evidence from a range of cancers suggests strongly that de novo expression of voltage-gated sodium channels (VGSCs) plays a significant role in driving cancer cell invasiveness. Under hypoxic conditions, common to growing tumours, VGSCs develop a persistent current (INaP) which can be blocked selectively by ranolazine.

Methods

Several different carcinomas were examined. We used data from a range of experimental approaches relating to cellular invasiveness and metastasis. These were supplemented by survival data mined from cancer patients.

Results

In vitro, ranolazine inhibited invasiveness of cancer cells especially under hypoxia. In vivo, ranolazine suppressed the metastatic abilities of breast and prostate cancers and melanoma. These data were supported by a major retrospective epidemiological study on breast, colon and prostate cancer patients. This showed that risk of dying from cancer was reduced by ca.60% among those taking ranolazine, even if this started 4 years after the diagnosis. Ranolazine was also shown to reduce the adverse effects of chemotherapy on heart and brain. Furthermore, its anti-cancer effectiveness could be boosted by co-administration with other drugs.

Conclusions

Ranolazine, alone or in combination with appropriate therapies, could be reformulated as a safe anti-metastatic drug offering many potential advantages over current systemic treatment modalities.

Clinical potential and conclusion

From the available evidence, taken together, we can propose that ranolazine could be utilised as an anti-metastatic drug [56]. Indeed, the evidence, at all levels from in vitro to human, is consistent for the role of ranolazine in suppressing cellular invasiveness and full-blown metastasis in several different carcinomas. Ranolazine has been in clinical use against angina pectoris for several years and, more recently, it has proven to be highly effective also against arrhythmia. Thus, it has a well-known dosage and safety profile. Nevertheless, some adverse side effects have been reported, including dizziness, headaches, nausea, debility and constipation [https://www.ncbi.nlm.nih.gov/books/NBK507828/]. Furthermore, it is recommended that ranolazine is not used together with some drugs such as other VGSC modulators (e.g., carbamazepine, phenytoin), as mentioned above for propranolol [31], antidepressants (e.g., nefazodone, amitriptyline), anticonvulsants (e.g., phenobarbital), CYP3A4 inhibitors (e.g., ketoconazole, diltiazem, verapamil), and anti-fungals/bacterials (e.g, itraconazole, ketoconazole, clarithromycin) [https://www.ncbi.nlm.nih.gov/books/NBK507828/]. There are also some reports of ranolazine inducing long QT, but this is likely to occur only at higher doses [57].

Another advantage of targeting INaP is the fact that the VGSC generating this current is essentially a functional biomarker. Accordingly, patients can readily be stratified by their profile of VGSC protein expression by immunohistochemical staining of their biopsies which is done routinely in hospital pathology laboratories. Ranolazine therapy would be appropriate only for patients whose biopsies were found to express VGSC protein. In this regard, we have already developed a polyclonal antibody specific for nNav1.5 [58] and a novel monoclonal antibody is currently being validated.

In overall conclusion, ranolazine has the potential to be readily adopted as an anti-metastatic drug, either by itself or in appropriate combination with a mechanistically compatible agent and this can be done as precision medicine. Further studies are justified to examine whether ranolazine could keep tumours in a localised state and thus enable patients to live with their cancer as a chronic disease, as with chronic angina.

Angina Drug No Help for Blocked Vessels Post-PCI

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Routine use of the anti-anginal drug ranolazine (Ranexa) for patients with blocked vessels remaining after percutaneous coronary intervention (PCI) didn’t reduce subsequent revascularization attempts or hospitalization, the RIVER-PCI trial showed.

The primary endpoint of ischemia-driven revascularization or other hospitalizations due to ischemia occurred in 26.2% receiving the drug versus 28.3% on placebo (P=0.95), Giora Weisz, MD, of Shaare Zedek Medical Center in Jerusalem and New York-Presbyterian/Columbia University Medical Center in New York City, and colleagues found.

Nor were there any differences in either components individually or for patient subgroups, including by age and severity of coronary disease, Weisz reported here at theTranscatheter Cardiovascular Therapeutics (TCT) meeting and simultaneously online in the Lancet.

Safety endpoints showed no differences between groups, except for an excess of transient ischemic attack (1.0% versus 0.2%, P=0.02) that he thought was a chance finding because of the lack of difference in stroke rate.

One reason for the failure could have been the “relatively high rate of study drug discontinuation,” Weisz suggested.

A panel of discussants at a TCT press conference where the findings were presented was more critical of the entire anti-anginal approach in this setting, though.

Bernard De Bruyne, MD, PhD, of Cardiovascular Center Aalst, Belgium, suggested that the target was probably wrong.

“These data might support the hypothesis that actually ischemia is not that important by itself,” he said. “What is important is the extent or the risk of having an acute occlusion. When there is ischemia, very often it means that something is wrong with an epicardial vessel, with a gradient, with physical forces … But ischemia, especially on relatively small territories, probably does not lead to problems.”

Weisz agreed with that possible explanation of the negative results. “It might be that incomplete revascularization by itself is a surrogate marker of the extent and burden of atherosclerosis,” he said.

“I believe that in the long run, we should go for anti-atherosclerotic treatment,” Nico H.J. Pijls, MD, PhD, of Catharina Hospital in Eindhoven, the Netherlands, commented. “Anti-anginal is just treating symptoms. Anti-atherosclerotic means taking away the cause, so you get much more long-term benefit.”

But he also added that the trial might have diluted any potential effect by selecting patients with good characteristics to begin with rather than additionally requiring fractional flow reserve results that suggest more room for impact.

The trial included 2,651 adults in 15 countries in Europe, Israel, Russia, and the U.S. who had a history of chronic angina, and after PCI, still had at least one lesion with at least 50% diameter stenosis in a 2-mm diameter or larger coronary artery. They were randomized to twice-daily oral ranolazine (1,000 mg) or matching placebo, starting at an average of 6.5 days after the initial PCI.

Both groups were well-treated otherwise with medications recommended in that setting, Weisz noted.

“The most common site-reported reasons for incomplete revascularization were the belief that medical treatment was an accepted approach for the degree of untreated atherosclerosis, that, angiographically, any residual lesions were unlikely to be clinically significant, and that percutaneous coronary intervention would have a low likelihood of acute success,” his group wrote in the Lancet paper.

Most of the lesions that led to ischemia-driven revascularizations were ones that had been successfully treated initially, then developed restenosis or stent thrombosis or had been previously present but not revascularized. “Fewer revascularisation events were due to new lesions that were not previously present or were nonobstructive (diameter stenosis <50%) at the time of randomisation,” the researchers noted.

Sanjit S. Jolly, MD, of McMaster University in Hamilton, Ontario, called the findings definitive.

“As a preventive strategy for patients who basically have been unrevascularized, it doesn’t prevent ischemia-driven revascularization,” he told reporters at the press conference. “However, ranolazine definitely is a useful therapy in patients with refractory angina. So that is an acceptable indication to still use it.”

TERISA: Ranolazine reduced angina in patients with diabetes.

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Results from an international trial demonstrate that ranolazine was safe and effective for patients with type 2 diabetes, coronary artery disease and persistent chronic angina.

Mikhail Kosiborod, MD, from St. Luke’s Mid America Heart Institute and University of Missouri, Kansas City, presented data that showed ranolazine (Ranexa, Gilead) significantly reduced angina frequency and sublingual nitroglycerin use, and as safe and well tolerated.

Following a single blind, 4-week placebo run-in phase, 949 patients were randomly assigned to 8 weeks of ranolazine (1,000 mg twice daily) or matching placebo. The mean age of the patients’ was 64 years; 61% were men; mean diabetes duration was 7.5 years; and mean baseline HbA1c was 7.3%.

“Ranolazine has previously been shown to be effective and may have the additional property of lowering HbA1c,” Kosiborod said at a press conference.

The primary endpoint was number of self-reported angina episodes between weeks 2 and 8. Weekly episodes of angina were reported less in patients assigned ranolazine compared with placebo (3.8 vs. 4.3; P=.008). A secondary endpoint was frequency of sublingual nitroglycerin use during the same study period. Self-reported use was also lower in the ranolazine group (1.7 doses per week vs. 2.1 doses per week; P=0.003).

Data indicate no difference in the incidence of serious adverse events between groups.

The researchers also found that ranolazine was especially effective in patients with worse glucose control.

“If the glucose-lowering action of ranolazine is confirmed in future studies, patients with diabetes and angina may derive a dual benefit from this drug,” Kosiborod stated in a press release.

The TERISA trial was conducted at 104 centers in 14 countries. At baseline, 43% of patients were taking one anti-angina agent and 57 were taking two anti-angina agents. The use of guideline-recommended therapy was high: 87% taking antiplatelet agents, 83% taking statins, 88% taking ACE inhibitors/angiotensin receptor blockers and 90% taking beta-blockers.

Compliance with self-reports in an electronic diary was 98% in both groups, Kosiborod said. – by Samantha Costa

For more information:

Kosiborod M. Late-breaking clinical trials III: Chronic CAD/stable ischemic heart disease. Presented at: American College of Cardiology Scientific Sessions; March 9-11, 2013; San Francisco.

Kosiborod M. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.02.011.

Disclosure: The study was funded by Gilead Sciences. Kosiborod reports consultancy fees/honoraria from Boehringer Ingelheim, CardioMEMS, Genentech, Gilead, Hoffman-La Roche, Kowa Pharmaceuticals, Medtronic Minimed and Sanofi-Aventis, and research grants from Genentech, Gilead, Glumetrics and Medtronic Minimed.

PERSPECTIVE

  • In many European countries, particularly in the countries that participated in this study, there is still more of a conservative approach to the management of patients with angina. They are stable, they use more medications and less interventions than we do in the United States.

Now, there are new criteria for revascularization and we are being encouraged to treat people medically — to treat them properly — if they respond to drugs. In the United States, we might be moving a little more in that direction.

Ranolazine already has been shown to be effective, so the question researchers were looking [to answer] was whether patients with diabetes benefit from this drug. Diabetics, as we know, have problems with reduction in coronary reserve, myocardial issues, diabetic cardiomyopathy, muscle stiffness and more.

The other interesting point is that patients with HbA1c levels greater than 7% had strikingly better effect response than those with HbA1c less than 7%. This becomes very interesting in terms of possible mechanisms exploring other areas.

  • Miguel A. Quinones, MD, MACC
  • Chairman of the ACC, 2013
    Professor of Medicine, Weill Cornell Medical College
    Chairman, Department of Cardiology, The Methodist Hospital
    Methodist DeBakey Heart & Vascular Center

Source: Endocrine Today.