Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels

Abstract

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 μM) paralleled by increased reactive oxygen species production and caspase activity. These effects were even more pronounced, when cells were incubated with MRS1477 (2 μM) either alone or together with CAPS (10 μM). Capsazepine, a TRPV1 blocker, inhibited both the effect of capsaicin and MRS1477. Whole-cell patch clamp recordings revealed that capsaicin-evoked TRPV1-mediated current density levels were increased after 3 days incubation with MRS1477 (2 μM). 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.

Anticancer Activity of Natural and Synthetic Capsaicin Analogs

“…The compound MRS1477 (Fig. 7F), a positive allosteric modulator of TRPV1, was found to be very robust in inducing apoptosis in human breast cancer cells in vitro and in athymic mouse model (Naziro glu et al, 2017). The growth-inhibitory effects of MRS1477 were observed at fivefold lower concentration relative to capsaicin.…”

“…The growth-inhibitory effects of MRS1477 were observed at fivefold lower concentration relative to capsaicin. The proapoptotic activity of MRS1477 was mediated by the TRPV1 receptor (Naziro glu et al, 2017).…”

Transient Receptor Potential Cation Channels in Cancer Therapy

“…The effects are TRPV1 specific, since CPZ inhibits both the effect of CPS and MRS1477. However, the tumor growth in MCF-7 tumor-bearing immunodeficient mice is not inhibited by MRS1477, suggesting that in vivo further studies are required [72].…”

Alterations in Calcium Signaling Pathways in Breast Cancer

“…TRPV6 had a high level of expression in breast adenocarcinoma tissue [87]. TRPV1 is functionally expressed in SUM149PT breast cancer cells, a model for a very aggressive form of breast cancer (i.e., triplenegative breast cancer) [88], and in MCF7 breast cancer cells [89,90].…”

“…To date, capsaicin inhibits cancer growth in SUM149PT breast cancer cells, by triggering apoptotic/necrotic mechanisms, while capsazepine diminishes these effects [88]. MRS1477, a positive allosteric modulator of TRPV1, when co-applied with capsaicin, diminished the fraction of MCF7 breast cancer apoptotic cells but was ineffective against tumor growth in MCF7 tumor-bearing immunodeficient mice [89]. Another study demonstrated that doxorubicin and melatonin exert synergistic effects against apoptosis and mitochondrial oxidative stress in MCF-7 breast cancer cells by activating TRPV1 [126].…”