Hypertension drugs increase the effect of chemo in childhood cancer

Beta-blockers are traditionally used in the treatment of high blood pressure, but researchers at the Children’s Cancer Institute Australia (CCIA) have found that they can also increase the effectiveness of chemotherapy in treating aggressive childhood cancers such as neuroblastoma.

The project was initiated by Dr Eddy Pasquier after receiving the Balnaves Foundation Young Researcher of the Year grant in 2010. He explained, “Retrospective studies have recently suggested that the use of beta‐blockers in cancer patients may be associated with clinical benefits. We therefore asked the question ‘could beta‐blockers be directly combined with chemotherapy to increase its efficacy in hard‐to‐treat cancers?’”

In the study, published in the British Journal of Cancer, the researchers outlined their method: “Seven beta-blockers were tested for their antiproliferative and antiangiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma.”

Three beta-blockers (carvedilol, nebivolol and propranolol) were found to exhibit potent anticancer properties in vitro and interacted synergistically with the mitotic inhibitor vincristine, used in chemotherapy, independently of P-glycoprotein expression. In vivo, the beta-blockers alone transiently slowed tumour growth, and when used in combination with vincristine they significantly increased tumour regression. This “ultimately resulted in a four-fold increase in median survival” in the test mice compared with vincristine alone, said the researchers.

Dr Pasquier said the drugs “increase the efficacy of certain types of chemotherapy used in the treatment of neuroblastoma … by promoting their capacity to block the formation of blood vessels within the tumour [this formation is known as angiogenesis]”. Not only are these drugs cheap and non-toxic, making them suitable for low- and middle-income countries, but Dr Pasquier said their effect could possibly reduce the dosage of chemotherapy required, thus also reducing its side effects on the patients.

A comment on the research was recently submitted to the British Journal of Cancer by Y Ji and S Chen, from West China Hospital of Sichuan University and Children’s Hospital of Fudan University respectively, calling for further discussion on the research. They say that cancer-derived endothelial cell (EC) lines exhibit high resistance to vincristine and angiogenesis inhibitors; thus “the possibility that neuroblastoma-derived ECs are chemotherapy-sensitive warrants further investigation”, as does their sensitivity to beta-blockers. They were also concerned about the dosage levels of beta-blockers used in the study, which were “10-50 and 500-5000 times those that used in paediatric patients during oral and intravenous treatment, respectively”, especially since many patients often go through expectant observation - a ‘wait and see’ period where treatment can be kept to a minimum.

Dr Pasquier and co-authors responded, noting that the three beta-blockers were consistently able to inhibit angiogenesis in vitro and “potentiate the antiangiogenic and antiproliferative effects of chemotherapy agents at concentrations that were 5- to 50-fold lower than those required to inhibit the proliferation of cancer cells when used alone”, thus showing that they are “potent antiangiogenic and chemo-sensitising agents, rather than true cytotoxic drugs”, more likely to be beneficial in combination with chemotherapy. They acknowledged that high doses of beta-blockers may bring unwanted side effects but said they may be “required to maximise the anticancer effects”; thus, further studies will need to address the optimal dosage.

As for non-high-risk patients, the researchers agree that their treatment should ideally be kept to a minimum. “However,” they said, “we advocate for the clinical investigation of the potential of beta-blockers to (i) further reduce treatment intensity in selected non-high-risk patients with unfavourable prognostic features, (ii) improve outcome of non-high-risk patients who fail observation or recur after surgery and (iii) salvage patients with relapsed and/or drug-refractory neuroblastoma tumours.”