Synthesis and Identification of Small Molecules that Potently Induce Apoptosis in Melanoma Cells through G1 Cell Cycle Arrest

Abstract

Late-stage malignant melanoma is a cancer that is refractory to current chemotherapeutic treatments. The average survival time for patients with such a diagnosis is 6 months. In general, the vast majority of anticancer drugs operate through induction of cell cycle arrest and cell death in either the DNA synthesis (S) or mitosis (M) phase of the cell cycle. Unfortunately, the same mechanisms that melanocytes possess to protect cells from DNA damage often confer resistance to drugs that derive their toxicity from S or M phase arrest. Described herein is the synthesis of a combinatorial library of potential proapoptotic agents and the subsequent identification of a class of small molecules (triphenylmethylamides, TPMAs) that arrest the growth of melanoma cells in the G1 phase of the cell cycle. Several of these TPMAs are quite potent inducers of apoptotic death in melanoma cell lines (IC(50) approximately 0.5 muM), and importantly, some TPMAs are comparatively nontoxic to normal cells isolated from the bone marrow of healthy donors. Furthermore, the TPMAs were found to dramatically reduce the level of active nuclear factor kappa-B (NFkappaB) in the cell; NFkappaB is known to be constitutively active in melanoma, and this activity is critical for the proliferation of melanoma cells and their evasion of apoptosis. Compounds that reduce the level of NFkappaB and arrest cells in the G1 phase of the cell cycle can provide insights into the biology of melanoma and may be effective antimelanoma agents.

Andrographolide inhibits proliferation and induces cell cycle arrest and apoptosis in human melanoma cells

“…Many anticancer agents inhibit tumor cell proliferation by causing G2/M cycle arrest, such as celastrol (27), ophiopogonin D (26). The G2 checkpoint regulats cell caryomitosis when DNA is destroyed, which provides repair opportunities for damaged cells (28,29). Our studies showed that Andro decreased the cell proportion in G0/G1 and S phases while Andro induced G2/M phase arrest in human malignant melanoma A375 and C8161 cell lines.…”

Synthesis, Characterization and Docking Studies of 4, 4’-Diaminotriphenylmethanes (DATPMs)

“…In the recent years, triarymethyl motif has been identified as anticancer agent in the mice cells. It has been shown that the triphenylmethyl containing compounds cause the death of melanoma cells in mice cells with reduced toxicity to normal cells of human bone marrow even high doses were tolerated by the mice cells [2]. Several new compounds with triarylmethyl groups have been designed and synthesized successfully.…”

TDiscovery and Development of Novel Therapeutic Agents for Advanced Melanoma

“…The natural role of melanocytes is to protect inner organs from UV light, a potent DNA damaging agent. Therefore, it is not surprising that melanoma cells may have special DNA damage repair systems and enhanced survival properties (79). Moreover, recent studies showed that, during melanoma progression, it acquired complex genetic alterations that led to hyperactivation of efflux pumps, detoxification enzymes, and a multifactorial alteration of survival and apoptotic pathways.…”

“…After 12 h, media were changed and serial dilutions of compounds were added (1 nM~100 M). Cells were incubated with each compound for 48 h. Fresh media containing the testing compound were changed every 24 h. Thereafter, total cell protein corresponding to cell numbers (both viable and non-viable cells) was measured using the sulforhodamine B (SRB) assay according to the manufacturer's protocol (Sigma-Aldrich Inc., St. Louis, MO) (79,90). Briefly, cells were fixed with trichloroacetic acid, washed, and incubated with sulforhodamine B for 30 min.…”