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An Introduction to the Ethnopharmacology of Wild Plants
Published in Mahendra Rai, Shandesh Bhattarai, Chistiane M. Feitosa, Ethnopharmacology of Wild Plants, 2021
Shandesh Bhattarai, Christiane Mendes Feitosa, Mahendra Rai
The first agents to advance into clinical use were the isolation of the vinca alkaloids, vinblastine, and vincristine from Catharanthus roseus, for the treatment of cancer followed by the discovery of paclitaxel from Taxus brevifolia (Kinghorn 1994, Kaur et al. 2011). Various parts of the Taxus have been used for the treatment of some noncancerous cases (Crag and Newmann 2005). Taxus baccata was also reported for the treatment of cancer. Paclitaxel is significantly active against ovarian cancer, advanced breast cancer, and lung cancer. Topotecan is used for ovarian and lung cancer from Xi shu tree [Camptotheca acuminata] (Steenhuysen 2007). Camptothecin, isolated from Camptotheca acuminate, is used for the treatment of ovarian and small cell lung cancers, and colorectal cancers (Kinghorn 1994, Creemer et al. 1996, Bertino 1997). Irinotecan is used for colon cancer treatment from Xishu tree [Camptotheca acuminate] (Online Medical Dictionary 2007). Epipodophyllotoxin was isolated as the active antitumor agent from the roots of Podophyllum species, Podophyllum peltatum and Podophyllum emodi, used in the treatment of lymphomas and bronchial and testicular cancers (Harvey 1999). The Podophyllum peltatum and P. emodii are used for the skin cancers.
Farnesyltransferase Inhibitors: Current and Prospective Development for Hematologic Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Etoposide is an epipodophyllotoxin with clinical activity against both newly diagnosed and relapsed leukemias, particularly when combined with other cytotoxic agents (71). Etoposide induces DNA double-strand and single-strand breaks by binding to and stabilizing the covalent linkage between topoisomerase II and DNA, and preventing religation of the resultant strand breaks (72). Because it targets topoisomerase II, it exerts its effects predominantly on cells in the S phase, with subsequent arrest in G2/M. In an attempt to increase CR rates in elderly AML patients, Karp et al. (73) have conducted a phase I trial of oral tipifarnib plus etoposide, with escalating doses of both drugs and 14 versus 21 days of tipifarnib every 28 to 63 days (median time to cycle 2 day 31, range 29–43 days). A total of 84 adults 70 years or older (median 77 years, range 71–91 years) were treated at 14 dose levels of tipifarnib (300, 400, or 600 mg twice daily, 14 or 21 days) + etoposide (100, 150, or 200 mg daily days 1–3 and 8–10) for a median two cycles (range 1–7 cycles). The majority (90%) had at least 1 comorbidity, and 40% had 3 or more comorbidities, 58% had secondary AML, and 54% had adverse cytogenetics. Hospitalization was necessary in 54% during cycle 1, but was only 28% for all cycles. Treatment-related mortality was 11%. Twenty-one (25%) achieved CR and an additional 13(15%) achieved PR/HI, for an overall response rate that approaches 40%. Median duration of CR so far is 10.5 months. Fifteen of forty-eight (31%) patients receiving tipifarnib greater than or equal to 400 mg BID versus 5/36 (14%) tipifarnib 300 mg BID and 16/54 (30%) receiving tipifarnib for 14 days versus 4/30 (13%) tipifarnib 21 days have achieved CR. Median age of CR patients is 77 years (range 71–86 years), and 8 (40%) had adverse cytogenetics. CR durations to date range from 2 to 27+ months. The mechanisms for the apparent synergistic interactions between tipifarnib and etoposide are not yet clear, but may relate in part to combined effects of both drugs on G2/M arrest and completion of mitosis. Indeed, the targeting of CENPs by tipifarnib may be one basis for the additive and/or synergistic interactions between tipifarnib and etoposide in terms of augmenting G2/M arrest, mitotic arrest and resultant cell death.
Cardiovascular safety of oncologic agents: A double-edged sword even in the era of targeted therapies – part 1
Published in Expert Opinion on Drug Safety, 2018
Antonis A. Manolis, Theodora A. Manolis, Dimitri P. Mikhailidis, Antonis S. Manolis
Topoisomerase inhibitors inhibit topoisomerase enzymes which reduce supercoiling of DNA and comprise two classes of drugs derived from natural sources, camptothecins and podophyllotoxins [121]. Their mechanism is analogous to that of the fluoroquinolone class of antibiotics. Camptothecins (topotecan, irinotecan) are plant alkaloids originally isolated from the Chinese tree Camptotheca, are S-phase specific and inhibit topoisomerase I, which is essential for the replication of DNA in human cells. Irinotecan and topotecan are semisynthetic derivatives of camptothecin. Topotecan is used in metastatic ovarian cancer and small cell lung cancer. Irinotecan is used with 5-FU and leucovorin for the treatment of colorectal carcinoma. The epipodophyllotoxin derivatives (etoposide, teniposide) inhibit topoisomerase II and their major clinical use is in the treatment of lung cancer, lymphomas and in combination with bleomycin and cisplatin for testicular carcinoma [122].
In vitro antimicrobial and anti-proliferative activities of plant extracts from Spathodea campanulata, Ficus bubu, and Carica papaya
Published in Pharmaceutical Biology, 2016
Jean Emmanuel Mbosso Teinkela, Jules Clément Assob Nguedia, Franck Meyer, Erik Vouffo Donfack, Bruno Lenta Ndjakou, Silvère Ngouela, Etienne Tsamo, Dieudonné Adiogo, Anatole Guy Blaise Azebaze, René Wintjens
Approximately 6% of the world’s plants have been screened for their biological activities, and just around 15% have been phytochemically evaluated (Verpoorte 2000; Fabricant & Farnsworth 2001; Li & Vederas 2009). Hence, plants are largely unexplored, despite their potentials as source of novel therapeutic agents with potent antibiotic and anticancer properties, although natural products have played a highly significant role in the discovery and development of drugs (Koehn & Carter 2005; Newman & Cragg 2007). In particular, the contribution of plants is immense in the field of cancer research, where about half of the available drugs are of natural origin (Mann 2002; Altmann & Gertsch 2007), some of which are powerful anticancer agents like camptothecin, epipodophyllotoxin (Kinghorn 2008), and paclitaxel (Altmann & Gertsch 2007). In addition, plants with active medicinal properties are readily available for local use and once their scientific validation and efficacy are established, their application are no longer based solely on folkloric recommendations (Akerele 1992).
Computational screening of chalcones acting against topoisomerase IIα and their cytotoxicity towards cancer cell lines
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Kanyani Sangpheak, Monika Mueller, Nitchakan Darai, Peter Wolschann, Chonticha Suwattanasophon, Ritbey Ruga, Warinthon Chavasiri, Supaporn Seetaha, Kiattawee Choowongkomon, Nawee Kungwan, Chompoonut Rungnim, Thanyada Rungrotmongkol
Chalcones have attracted attention because of their promising therapeutic effects, since they are able to target multiple cellular molecules, such as MDM2/p53, tubulin, proteasome, NF-κB, TRIAL/death receptors and mitochondria-mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ, β-catenin/Wnt34 and especially hTopoIIα24,35–37. Moreover, epipodophyllotoxin–chalcone hybrids exhibited an enhanced in vitro cytotoxicity and higher topoisomerase II inhibitory efficiency than etopoiside38. A series of chalcone-triazole derivatives presented a promising anticancer activity against the A-549 cell line and showed high binding affinities towards DNA topoisomerase IIα and α-glucosidase targets39. Moreover, the novel bis-fluoroquinolone chalcone-like derivatives were found to inhibit both hTopoIIα and tyrosine kinase40. Recently, a series of 2′- and 4′-aminochalcones were found to inhibit the growth of a canine malignant histiocytic cell line (DH82) and the transcription of the hTopoIIα and TP53 genes41. In the present study, in order to find new potential anti-cancer agents against hTopoIIα, the new 47 chalcone derivatives were designed (Figure 2) and then screened in silico using a molecular docking approach. The potent chalcones with a more favorable interaction energy than that of the known hTopoIIα inhibitors were then synthesised and tested for their in vitro cytotoxicity towards three cell lines derived from urinary bladder (HT-1376), cervical (HeLa) and breast (MCF-7) cancers. Then, all-atom molecular dynamics (MD) simulations were performed to investigate the structure and dynamics properties as well as the ligand–target interactions between the most potent chalcone and hTopoIIα.