Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer

Abstract

New strategies are needed to treat cancers that do not respond to chemotherapy or resist chemotherapy after responding initially. The objective of this study was to evaluate non-cytotoxic drugs against two of these cancers, melanoma and ovarian cancer. Imiquimod is an immune stimulant that induces apoptosis in cancer cells. Flexible-Heteroarotinoids (Flex-Hets) are small molecules that regulate growth, differentiation and apoptosis in cancer cells with reduced effects on normal cells. Both imiquimod and SHetA2 inhibited growth and induced apoptosis in the B16 melanoma cell line and cisplatin-sensitive A2780 and cisplatin-resistant OVCAR-3 ovarian cancer cell lines. The growth inhibition was additive in A2780 and B16, and synergistic in OVCAR-3. Both compounds inhibited endothelial tube branching in vitro and exerted an additive effect when combined. Various combinations of imiquimod and SHetA2 did not cause significant differences in the overall survival in the syngeneic B16 murine melanoma model. SHetA2 induced complete tumor regression and a melanoma-free natural life-span in two mice. These cures occurred in one of ten mice treated with oral SHetA2 and one of ten mice intratumorally-injected with SHetA2. Exploratory modeling of the distribution of survival times suggested that the two surviving mice represent rare events. Histologic evaluation of the tumors revealed that imiquimod induced necrosis, SHetA2 induced differentiated architecture and increased cytoplasm, both agents reduced mitotic indices and angiogenesis and neither agent counteracted the effects of the other. No overt toxicities were observed. In conclusion, imiquimod and SHetA2 exhibit complementary anti-cancer activity in vitro and SHetA2 has promise as a single agent.

Optimization of a Vaginal Suppository Formulation to Deliver SHetA2 as a Novel Treatment for Cervical Dysplasia

“…The levels of cyclin D1 in tissues were evaluated as pharmacodynamic end point to confirm if SHetA2 concentrations in tissue were indeed able to induce an effect at tissue level 9 . SHetA2 induces phosphorylation, ubiquitination and proteasomal degradation of cyclin D1 that leads to G1 cell cycle arrest in multiple cancer cell lines 6, 18, 52 . It is also reported that, as cervical dysplasia progresses to invasive cancer, the expression of cyclin D1 increases.…”

SHetA2 interference with mortalin binding to p66shc and p53 identified using drug-conjugated magnetic microspheres

“…Pre-clinical testing for our lead compound, a flexible heteroarotinoid (Flex-Het) called Sulfur Het A2 (SHetA2, NSC721689) demonstrated reasonable pharmacokinetics and lack of mutagenicity, carcinogenicity, teratogenicity and toxicity [ 1 – 5 ]. SHetA2 has a wide therapeutic window as indicated by the No Observed Adverse Effect Level (NOAEL) of >1,500 mg/kg/day identified in the 28 day dog toxicity model in comparison to the ability of 10 to 60 mg/kg/day to inhibit xenograft tumor growth [ 5 – 8 ]. This lack of in vivo toxicity, along with oral bioavailability and documented inhibition of colorectal tumorigenesis in the APC min/+ mouse model at 30 mg/kg given 5 days per week, make SHetA2 an ideal candidate for a cancer prevention drug [ 9 ].…”