NEO412: A temozolomide analog with transdermal activity in melanoma in vitro and in vivo

Abstract

Despite new treatments introduced over the past several years, metastatic melanoma remains difficult to cure. Although melanoma in situ (MIS) has better prognosis, it relies heavily on thorough surgical excision, where ill-defined margins can pose a challenge to successful removal, potentially leading to invasive melanoma. As well, MIS in the head and neck area can create serious aesthetic concerns with regard to the surgical defect and substantial scar formation. Toward improved treatment of localized melanoma, including the targeting of unrecognized invasive components, we have been studying a novel agent, NEO412, designed for transdermal application. NEO412 is a tripartite agent that was created by covalent conjugation of three bioactive agents: temozolomide (TMZ, an alkylating agent), perillyl alcohol (POH, a naturally occurring monoterpene with anticancer properties), and linoleic acid (LA, an omega-6 essential fatty acid). We investigated the anti-melanoma potency of NEO412 in vitro and in mouse models in vivo. The in vitro results showed that NEO412 effectively killed melanoma cells, including TMZ-resistant and BRAF mutant ones, through DNA alkylation and subsequent apoptosis. in vivo, NEO412 inhibited tumor growth when applied topically to the skin of tumor-bearing animals, and this effect involved a combination of increased tumor cell death with decreased blood vessel development. At the same time, drug-treated mice continued to thrive, and there was no apparent damage to normal skin in response to daily drug applications. Combined, our results present NEO412 as a potentially promising new treatment for cutaneous melanoma, in particular MIS, deserving of further study.

The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers

“…In a mouse model of subcutaneous melanoma, topical application of NEO412 increased tumor cell death, along with decreased neo-angiogenesis in tumor tissue. Intriguingly, these effects could also be observed in tumors that were located distant from the skin treatment site, indicating that topical NEO412 was able to enter the circulation and reach tumor cells that might have metastasized already [201]. Although it remains to be established how much each penetration enhancer, i.e., POH vs. linoleic acid, contributed to transdermal migration of the tripartite molecule, the significant anti-melanoma effect that was achieved clearly indicates the benefit of this combination.…”

“…NEO412 is a tripartite agent consisting of three bioactive agents: POH, TMZ, and linoleic acid, with the latter representing a well-established transdermal penetration enhancer [199,200]. In vitro studies confirmed that NEO412 was able to effectively kill melanoma cells through the alkylation effect of TMZ [201]. In a mouse model of subcutaneous melanoma, topical application of NEO412 increased tumor cell death, along with decreased neo-angiogenesis in tumor tissue.…”

Selected Monocyclic Monoterpenes and Their Derivatives as Effective Anticancer Therapeutic Agents

“…This effect included a combination of increased tumor cell death with only minor blood vessel development. Drug-treated mice exhibited no apparent damage relative to healthy skin in response to periodic drug application [ 48 ].…”

“…with only minor blood vessel development. Drug-treated mice exhibited no apparent damage relative to healthy skin in response to periodic drug application [48]. Two novel amide derivatives 24 and 25 of (S)-perillic acid (Figure 12) were designed and synthesized.…”

“…In melanoma cells, the propane-1,2-diyl spaced with a terpene moiety of (−)-menthol derivative 48b and (+)-neomenthol derivative 48l displayed growth inhibition at an IC 50 < 4 µM, which is 10-fold lower than seen with cisplatin (Table 1). Furthermore, presented terpene complexes (48,49) were tested for antiproliferative activity in human HT-29 colon cells. Greater and more persistent growth inhibition in HT-29 colon cancer cells upon long-term exposure is induced by the (−)-menthyl ester complexes with 2,3-diaminopropanoate (49a) and 2,4diaminobutanoate (49b) ligands compared with the 6-(aminomethyl)nicotinate analogue 48a.…”