An analog of the drug naftopidil — used as a prostate hyperplasia and hypertension therapy — appears capable of knocking down pleural mesothelioma cells.
Researchers in Japan who made this discovery said that this analog could present a “brilliant hope” for mesothelioma patients.
The naftopidil analog goes by the shorthand name of HUHS1015. In full, its name is 1-[2-(2-Methoxyphenylamino) ethylamino]-3-(naphthalene-1-yloxy) propan-2-ol.
Here are the primary things the researchers learned from their investigation into HUHS1015 and wrote about in the Dec. 19, 2014, issue of the journal Molecules. Basically, HUHS1015:
- Activates caspase-8 by up-regulating tumor necrosis factor alpha — TNFα
- Induces caspase-independent apoptosis by accumulating a particular type of mitochondrion in the nucleus of mesothelioma cells
- Induces necroptosis of a variety of other cancer cells besides mesothelioma
- Suppresses tumor growth in mice.
Regular naftopidil — not the synthesized analog with which the researchers experimented — causes prostate cancer cell growth to come to a halt during the G1 phase of cell cycling.
However, the mechanism by which naftopidil accomplishes this is not well understood.
What science does understand about naftopidil is that it is an antagonist for the α1-adrenoceptor.
They also know it has high selectivity for the α1A- and α1D-receptors protruding from the surface of the α1-adrenoceptor.
Both α1-adrenoceptor sub-types are linked to Gq/11 protein-bearing phospholipase C activation, which is followed by protein kinase C activation.
The researchers theorize that protein kinase C activation is suppressed by naftopidil, which in turn disrupts the operation of the entire α1-adrenoceptor mechanism.
The disruption inhibits the growth of cancer cells, suggested lead author Tomoyuki Nishizaki, M.D., of Hyogo College of Medicine, Nishinomiya.
Tested Against Mesothelioma
Nishizaki and his colleagues created not just a single synthesized naftopidil analogue but a total of 21 of them.
They then tested the anticancer effect of each against a number of human malignant pleural mesothelioma cell lines, including NCI-H28, NCI-H2052, NCI-H2452 and MSTO-211H.
It turned out that HUHS1015 worked the best of any of the 21 synthesized naftopidil analogues. It also worked against other types of cancer cells, those unrelated to mesothelioma.
“HUHS1015 induces both necrosis — or necroptosis — and apoptosis,” the researchers wrote.
“The former may be caused by intracellular ATP reduction in association with mitochondrial damage or activation of the RIP1 kinase.
“The latter may be due to caspase activation through the mitochondria and TNFα receptor for caspase-dependent apoptosis, and to mitochondrion accumulation in the nucleus for caspase-independent apoptosis.”
HUHS1015 Triggers Mesothelioma Apoptosis
In the mice they tested, HUHS1015 effectively prevented tumor growth. They also found the opposite to be true — that if they withdrew HUHS1015, mesothelioma cells started growing again.
Actual testing of HUHS1015 involved subjecting the selected mesothelioma cell lines to 12 hours of contact with the synthesized compound.
Afterward, the researchers were able to determine that HUHS1015 effectively suppressed tumor growth.
It did so to an extent that made it appear the compound could be at least as successful as other currently used anticancer drugs, and possibly more successful — much more successful.
“HUHS1015 could be developed as an efficient anticancer drug,” the scientists concluded.