Cytotoxicity of sphingoid marine compound analogs in mono- and multilayered solid tumor cell cultures

Abstract

A subset of four synthetic sphingoid marine compound analogs was chosen from a preliminary in vitro cytotoxicity study for further analysis. The selected analogs were initially screened in monolayer cultures for their anticancer potential against a panel of eight human tumor cell lines, ovarian, colon and lung cancer, squamous cell carcinoma and leukemia producing IC50 values ranging from 1.5 to 6.9 microM. In a secondary screening, the sphingoid analogs were evaluated against multilayered postconfluent cultures of A2780 ovarian cancer and WiDr colon cancer cells. In this model, compounds 5 and 8 were the most active derivatives showing EC50 values in the range 25-32 microM. The performance of 5 and 8 against both cell lines was not dependent on the cell culture model as shown with resistance factor values in the range 8-12. Cell cycle studies in HL60 leukemia cells showed an arrest in G(0)/G1 at a low drug concentration (3 microM) but accumulation in S phase at a high drug concentration (9 microM). It can be concluded that the analogs showed a cell line independent activity, with an apparent selectivity against cells grown in more physiological three-dimensional condition compared to standard anticancer drugs.

Sphingolipids in Anticancer Therapy

“…However, either saturated (43−46) or unsaturated (47−50) sphingosine analogs gave similar anticancer activity. An additional point of difference was found for amino alcohol (51), which showed in HL60 cells an IC 50 Similar results were observed for compounds (46, 48, 50−51) against panel of eight human tumor cell lines from diverse origin [104]. However, the study of the anticancer activity in postconfluent multilayered cultures [105] of A2780 and WiDr cells revealed differences between the compounds.…”

“…The multilayer model offers a unique opportunity to study the structural requirements for activity in a three-dimensional cell culture system. Compounds (50− 51) were the most active substances in this cell culture model [104]. In HL60 leukemia cells the most common observed effects were arrest in G 0 /G 1 at low drug dose and accumulation in the S phase in high drug dose.…”

The anti-tumor activities of cerebrosides derived from sea cucumber <i>Acaudina molpadioides</i> and starfish <i>Asterias amurensis in vitro</i> and <i>in vivo</i>

“…The marine environment is a source of extremely potent natural products that have confi rmed signifi cant activity as anti-tumor and tumor cells cytotoxic drugs 31 . Carcinogenesis is a multistep process in which an accumulation of genetic alterations within a single cell line leads to a progressively dysplastic cellular appearance deregulated cell growth, and finally carcinoma 32 .…”

Enigmol: A Novel Sphingolipid Analogue with Anticancer Activity against Cancer Cell Lines and In vivo Models for Intestinal and Prostate Cancer

“…A longer persistence of the free sphingoid base might also contribute to the cytotoxicity of the synthetic analogs safingol (38), N,N-dimethylsphingosine (39) and naturally occurring sphingoid base variants (40, 41), including one recently evaluated in a Phase I trial (42). …”