Dormant tumor cells interact with memory CD8+ T cells in RET transgenic mouse melanoma model.

Melanoma is an aggressive form of skin-cancer. Melanoma cells are characterized by their plasticity, resulting in therapy resistance. Using RET transgenic mouse melanoma model, we characterized dormant tumor cells accumulated in the bone marrow (BM) and investigated their interaction with effector memory CD8+ T cells. We found that cells expressing melanoma-associated antigen tyrosinase related protein (TRP)-2 and stemness marker CD133 represented less than 1.5% of all melanoma cells in primary skin lesions and metastatic lymph nodes. The majority of these cells were negative for the proliferation marker Ki67. In the BM, CD133+TRP-2+ melanoma cells displayed an aberrant expression of p16, p27, Ki67 and PCNA proteins, suggesting their dormant phenotype. Moreover, these cells were characterized by an elevated expression of various molecules characterized stemness, metastatic, angiogenic and immunosuppressive properties such as CD271, CD34, HIF-1α, CXCR3, CXCR4, VEGR2, PD-L1, CTLA-4, CD39 and CCR4 as compared to their CD133- counterparts. Disseminated BM dormant TRP-2+ tumor cells were found to be co-localized with memory CD8+ T cells. Our data suggest that these dormant melanoma cells in the BM could play an important role in the maintenance of memory T cells in the BM.

Apoptotic, necrotic, and antiproliferative activity of diosgenin and diosgenin glycosides on cervical cancer cells.

(25R)-spirost-5-en-3ß-ol, also known as diosgenin (DSG), exerts antiproliferative activity on diverse cell lines, induces apoptosis, and acts as a chemopreventative agent. However, the relationship between DSG glycosides and apoptotic, necrotic, and antiproliferative activity remains unclear. It is in this regard that we report the antiproliferative, necrotic, and apoptotic activities of DSG and its glycoside derivatives: (25R)-spirost-5-en-3ß-yl O-ß-D-glucopyranoside (3GD), (25R)-spirost-5-en-3ß-yl O-α-L-rhamnopyranosyl-(1 â†’ 4)-ß-D-glucopyranoside (3GRD); and (25R)-spirost-5-en-3ß-yl O-α-L-rhamnopyranosyl-(1 â†’ 2)-O-[α-L-rhamnopyranosyl-(1 â†’ 4)]-ß-D-glucopyranoside), also known as dioscin (DSC), in in vitro assays of cervical HeLa and CaSki cancer cells. The results demonstrated that DSG glycosidic derivatives preserved their antiproliferative activity. However, in both cancer cell lines, 3GD and 3GRD were less potent than DSG, while DSC was more potent than DSG. With respect to necrotic activity, all tested compounds showed no or low activity on the two cervical cancer cell lines. Regarding apoptosis, the results showed that DSG glycosides were better apoptosis-inducers than DSG, suggesting that glucose and rhamnose residues play a central role in enhancing the apoptotic activity of DSG. Finally, DSG and its glycosidic derivatives were shown to affect the proliferative potential of lymphocytes (non-tumour cells) to a lesser extent than cancer cells, suggesting that these compounds have selective action. In conclusion, the results indicate that DSG and its glycosidic derivatives are promising anticancer compounds since they are compounds with low necrotic activity and selective action.

Antiproliferative, cytotoxic and apoptotic activity of the bentonite transformation of sesquiterpene lactone glaucolide B to 5ß-hydroxy-hirsutinolide on tumor cell lines.

Numerous chemical compounds isolated from medicinal plants have anti-tumor properties, the effects of which on human cancer cells are currently under study. Here, the chemical transformation of glaucolide B were performed to produce a hirsutinolide. The antiproliferative and cytotoxic activity of 5ß-hydroxy-hirsutinolide and its ability to induce apoptosis in tumor and non-tumor cells (lymphocyte cultures and the normal HaCaT cell line) (1a) are reported. We ascertained that compound 1a exerts an inhibitory effect on the proliferation of SK-Lu-1, MDA-MB-231 and CaSki cells in a dose-dependent manner at IC50 values of 15, 18 and 30 µg/ml, respectively. The proliferation of lymphocyte cells treated with 1a was inhibited at a range from 14 to 28%, but the HaCaT cell line was not affected, suggesting that compound 1a has a selective action. Cytotoxic activity was evaluated by detecting the lactate dehydrogenase enzyme in supernatants from tumor and non-tumor cells. The 1a compound exhibited low or null cytotoxic activity in both cell types. The presence of apoptotic bodies and active caspase-3 in tumor cell lines treated with compound 1a are suggestive of apoptotic cell death. Notably, flow cytometry evaluation did not detect the presence of active caspase-3 on lymphocytes treated with this compound. Our results suggest that 5ß-hydroxy-hirsutinolide is a molecule with antiproliferative activity and low cytotoxic activity in tumor and non-tumor cells; this induces apoptotic cell death in tumor cell lines through selective action. Hence, this lactone could be considered a molecule worthy of study as an anti-tumor agent with therapeutic potential.

Quercetagetin and Patuletin: Antiproliferative, Necrotic and Apoptotic Activity in Tumor Cell Lines.

Quercetagetin and patuletin were extracted by the same method from two different Tagetes species that have multiple uses in folk medicine in Mexico and around the globe, one of which is as an anticancer agent. Their biological activity (IC50 and necrotic, apoptotic and selective activities of these flavonols) was evaluated and compared to that of quercetin, examining specifically the effects of C6 substitution among quercetin, quercetagetin and patuletin. We find that the presence of a methoxyl group in C6 enhances their potency.