There is convincing epidemiological and experimental evidence that capsaicin, a potent
natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist,
has anticancer activity. However, capsaicin cannot be given systemically in large
doses, because of its induction of acute pain and neurological inflammation. MRS1477,
a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if
added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477
evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial
cells. This indicates that MCF7 cells not only express functional TRPV1 channels,
but also produce endogenous TRPV1 agonists. We investigated the effects of MRS1477
and capsaicin on cell viability, caspase-3 and -9 activities and reactive oxygen species
production in MCF7 cells. The fraction of apoptotic cells was increased after 3 days
incubation with capsaicin (10 mu M) paralleled by increased reactive oxygen species
production and caspase activity. These effects were even more pronounced, when cells
were incubated with MRS1477 (2 mu M) either alone or together with CAPS (10 mu M).
Capsazepine, a TRPV1 blocker, inhibited both the effect of capsaicin and MRS1477.
Whole-cell patch clamp recordings revealed that capsaicinevoked TRPV1-mediated current
density levels were increased after 3 days incubation with MRS1477 (2 mu M). However,
the tumor growth in MCF7 tumor-bearing immunodeficient mice was not significantly
decreased after treatment with MRS1477 (10 mg/kg body weight, i.p., injection twice
a week). In conclusion, in view of a putative in vivo treatment with MRS1477 or similar
compounds further optimization is required.