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.

Multicomponent synthesis of some new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro anti-proliferative activity against CaSki, MDA-MB-231 and SK-Lu-1 tumour cells as apoptosis inducing agents without necrosis.

Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile.

Antiproliferative, Cytotoxic, and Apoptotic Activity of Steroidal Oximes in Cervicouterine Cell Lines.

Steroidal sapogenins have shown antiproliferative effects against several tumor cell lines; and their effects on human cancer cells are currently under study. Changes in the functionality on the steroidal structure make it possible to modify the biological activity of compounds. Herein, we report the synthesis and in vitro antitumor activity of two steroidal oxime compounds on cervical cancer cells. These derivatives were synthesized from the steroidal sapogenin diosgenin in good yields. The in vitro assays show that the steroidal oximes show significant antiproliferative activity compared to the one observed for diosgenin. Cell proliferation, cell death, and the cytotoxic effects were determined in both cervical cancer cells and human lymphocytes. The cancer cells showed apoptotic morphology and an increased presence of active caspase-3, providing the notion of a death pathway in the cell. Significantly, the steroidal oximes did not exert a cytotoxic effect on lymphocytes.

Cervical cancer cells induce apoptosis in TCD4+ lymphocytes through the secretion of TGF-ß.

PURPOSE: Tumor cells are known to secrete cytokines that modify their microenvironment in order to favor their survival and continuous proliferation. In this work, we evaluated if TGF-ß secreted in vitro by cervical cancer cells could interfere with the proliferation and survival of lymphocytes. METHODS: Lymphocytes were obtained from peripheral blood of healthy human volunteers, and isolated by density gradient centrifugation and cultured in 96-well plates. Lymphocyte proliferation was induced with phytohemaglutinin and co-cultured with conditioned media (CM) from cervical cancer cell lines, and the inhibition of proliferation was evaluated after 72 h by the incorporated radioactivity and a CFSE-labeling assay. TGF-ß quantification on these CM was evaluated by ELISA. Non-apoptotic cellular death was evaluated through disruption of cell membrane integrity by measuring the liberation of lactate dehydrogenase. The apoptosis process was evaluated by annexin-V and active caspase-3. The presence of CD4+ or CD8+ lymphocytes was evaluated by flow cytometry using specific antibodies. RESULTS: It was found that the conditioned media from these cells significantly inhibited the proliferation of lymphocytes and induced them to go into apoptosis. Antibodies against TGF-ß almost completely blocked this activity, suggesting that this cytokine is responsible for the inhibitory activity. When the induced apoptosis on subpopulations of lymphocytes was evaluated, it was detected that the CD4+ cells were specifically targeted. CONCLUSIONS: Cervical cancer cells secrete TGF-ß that inhibits lymphocyte proliferation and induces apoptosis in CD4+, but not in CD8+ lymphocytes.

Synthesis of 26-hydroxy-22-oxocholestanic frameworks from diosgenin and hecogenin and their in vitro antiproliferative and apoptotic activity on human cervical cancer CaSki cells.

Certain steroidal compounds have demonstrated an antiproliferative effect against several tumor cell lines; however, their complete role on cancer cells is not currently established. Herein, we report the synthesis and evaluation of two new 26-hydroxy-22-oxocholestanic steroids on cervical cancer CaSki cells. The title compounds were prepared from diosgenin and hecogenin in excellent yields. We determined their effect on cell proliferation, cell cycle, and cell death. The cytotoxic effect of the title compounds on CaSki and human lymphocytes was also evaluated, indicating that the main cell death process is not necrosis; the null effect on lymphocytes implies that they are not cytotoxic. The observation of apoptotic bodies as well as the increase in the expression of active caspase-3 along with the fragmentation of DNA confirmed that such new cholestanic frameworks induced apoptosis in tumor cells. Significantly, their antiproliferative activity on tumor cells did not affect the proliferative potential of normal fibroblasts from cervix and peripheral blood lymphocytes. The title compounds show selective antitumor activity and therefore serve as promising lead candidates for further optimization.

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.

Identification of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate-nitrostyrene hybrid as potent antiproliferative and apoptotic inducing agent against cervical cancer cell lines.

The present study seeks to describe the design and synthesis of six new Michael adducts of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate with nitrostyrenes and their in vitro antiproliferative activity against human cervical cancer cell lines [HeLa (HPV 18 positive), CaSki (HPV 16 positive) and ViBo (HPV negative) cervical cancer cell lines]. Virtual screening of the physicochemical properties of all compounds have also been presented. All the compounds exploited significant antiproliferative activity on the three cervical cancer cell lines. Compound 8a was found to be most potent, displaying in vitro antiproliferative activity against HeLa, CaSki and ViBo cervical cancer cell lines superior to Cisplatin and Paclitaxel with IC50 values 0.99 ±â€¯0.007, 2.36 ±â€¯0.016 and 0.73 ±â€¯0.002 µM respectively. In addition, compound 8a did not trigger the necrosis cell death to the test cancer cell lines. Further mechanistic study revealed that compound 8a could inhibit the cancer cell proliferation by inducing apoptosis through caspase-3 activation. Moreover, cell cycle analysis indicated that compound 8a could arrest the cell cycle at the G1 phase for HeLa and CaSki cancer cells. At the predetermined IC50 values on cancer cells, compound 8a did not induce any necrotic (cytotoxic) death to the normal human lymphocytes. In the present design, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane system was found to be superior than the piperazine counterpart 11.

Evaluation of the antitumour activity of Rinvanil and Phenylacetylrinvanil on the cervical cancer tumour cell lines HeLa, CaSKi and ViBo.

Capsaicin is a potent inducer of apoptosis in tumourreceptor potential vanilloid 1 (TRPV1). The present study determined the IC50 and cytotoxic and apoptotic activities of the Capsaicin analogues Rinvanil and Phenylacetylrinvanil (PhAR) on three cervical cancer cell lines: HeLa, CaSKi and ViBo. These analogues possess an increased affinity for TRPV1 receptors. The IC50 obtained proved to be cytotoxic for all three cell lines; however, in the cells treated with Capsaicin both active caspase-3 and nuclear fragmentation were present. Capsaicin and its analogues also inhibited the normal proliferation of lymphocytes, suggesting that they are non-selective antitumour compounds. Finally, we discuss the possible loss of the relation between apoptosis and affinity to TRPV1, and the need for other strategies to synthesise Capsaicin analogues that can be useful in cancer treatments.

Probing the selective antitumor activity of 22-oxo-26-selenocyanocholestane derivatives.

Diverse steroidal compounds have shown antiproliferative activity on certain tumor cell lines; however, their complete role on cancer cells has not been extensively established since the research is quite recent. Hence, deeper study in this field is required. Due to the importance of selenium in animal and human health; herein, we report the synthesis, characterization, and biological evaluation of two novel 22-oxo-26-selenocyanocholestanic steroids on cervicouterine cancer cells and non-tumor cells. The title compounds were straightforward prepared from diosgenin and hecogenin in excellent overall yields. We determined their effect on cell proliferation on HeLa, CaSki, and ViBo cell cultures. Their cytotoxic effect on tumor cells, as well as on peripheral blood lymphocytes was also evaluated. The increase in the expression of active caspase-3 along with the fragmentation of DNA confirm that the new 22-oxo-26-selenocyanocholestane frameworks potentiate apoptosis in tumor cells. The antiproliferative activity on tumor cells affects to some extent the proliferative potential of peripheral blood lymphocytes, so an immunosuppressive effect has also been established. The novel 22-oxo-26-selenocyanocholestane compounds show selective antitumor activity and therefore are promising lead candidates for further in vivo evaluation.

Synthesis and selective anticancer activity of steroidal glycoconjugates.

The synthesis of glucosamine derivatives of the steroidal sapogenins diosgenin and hecogenin using the N-phthaloyl protected trichloroacetimidate of d-glucosamine as donor and TMSOTf as promoter is reported. The corresponding glycoconjugates were transformed into their acetamido derivatives and the hydrochloride salt (from diosgenin) and tested against HeLa, CaSki, and ViBo cervicouterine cancer cells. These compounds showed low cytotoxicity values on tumor cells and human lymphocytes, indicating that the main cell death process is presumably not necrosis. Significantly, the antiproliferative activity of these compounds on tumor cells did not affect the proliferative potential of peripheral blood lymphocytes.

Synthesis and biological evaluation of the glycoside (25R)-3ß,16ß-diacetoxy-22-oxocholest-5-en-26-yl ß-d-glucopyranoside: a selective anticancer agent in cervicouterine cell lines.

The synthesis and biological evaluation of the new cholestane glycoside (25R)-3ß,16ß-diacetoxy-22-oxocholest-5-en-26-yl ß-d-glucopyranoside starting from diosgenin is described. This compound showed selective antiproliferative activity against CaSki, ViBo, and HeLa cervicouterine cancer cells. Its effect on the cell-cycle was determined. The cytotoxic effects of the title compound on cervicouterine cancer cell lines and human lymphocytes indicate that the main cell death process is not necrosis; hence it is not cytotoxic. The title compound induced apoptosis in cervicouterine cancer cells. Importantly, the antiproliferative activity on tumor cells did not affect the proliferative potential of peripheral blood lymphocytes. The title compound showed selective antitumor activity and greater antiproliferative activity than its aglycon, and therefore serves as a promising lead candidate for further optimization.

Synthesis of the steroidal glycoside (25R)-3ß,16ß-diacetoxy-12,22-dioxo-5α-cholestan-26-yl ß-D-glucopyranoside and its anti-cancer properties on cervicouterine HeLa, CaSki, and ViBo cells.

The synthesis of the new glycoside (25R)-3ß,16ß-diacetoxy-12,22-dioxo-5α-cholestan-26-yl ß-D-glucopyranoside starting from hecogenin is described. This compound showed anti-cancer activity against cervicouterine cancer cells HeLa, CaSki and ViBo in the micromolar range. Its effect on cell proliferation, cell cycle and cell death is also described. The cytotoxic effect of the title compound on HeLa, CaSki and ViBo cells and human lymphocytes was evaluated through the LDH released in the culture supernatant, indicating that the main cell death process is not necrosis; the null effect on lymphocytes implies that it is not cytotoxic. The ability of this novel glycoside to induce apoptosis was investigated; several apoptosis events like chromatin condensation, formation of apoptotic bodies, as well as the increase in the expression of active caspase-3 and the fragmentation of DNA confirmed that the compound induced apoptosis in cervicouterine cancer cells. Significantly, the antiproliferative activity on tumor cells did not affect the proliferative potential of normal fibroblasts from cervix and peripheral blood lymphocytes. The glycoside showed selective antitumor activity and greater antiproliferative activity than its aglycon; it therefore serves as a promising lead candidate for further optimization.