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THE PROGRESS OF USING CHINESE HERBAL MEDICINES IN CANCER RESEARCH
Published in Kevin Chan, Henry Lee, The Way Forward for Chinese Medicine, 2001
radicals formation, down-regulating the apopotic genes, affect hor-mones and ions transport, or cause DNA strands break (Table 8.1). Apoptosis or "programmed cell death" represents a mode of cell death during which the cell activity participates in self-destruction (see review Arends et al. 1990, Gorczyca et al. 1993). It has been identified by the internucleosomal DNA cleavage, which appears to be associated with endonuclease activation. Camptothecin from Camptotheca accuminata is a prototypical DNA topoisomerase I interactive agent which kills cancer cells by breaking the DNA strands leading to cell death by apoptosis (Traganos et al. 1996, Palissot et al. 1996). Topotecan and 9- Amino-20 (S)-camptothecin (9-AC), the analogs of camptothecin, are now being tested in Phase I clinical trail for leukemia and in Phase II trail for the metastatic breast cancer in the US (Eder et al. 1996). Paclitaxel, an analog of taxol from the Taxuss chinensisspp (Goldirsch et al. 1998, Lee et al. 1998), is also being currently tested in clinical trial as an apoptotic drug. Pharmacological studies demonstrated that curcumin is an antimutagen as well as an antipromoter for cancer (Hanif et al. 1997, Anto et al. 1996). The anticancer effect of curcumin is related to its ability to accumulate cells in the G2/M phase, inhibition on prostaglandin synthesis, as well as antioxidant property (Hanif et al. 1997). Cucumin also induces cell death through suppression of the cell death genes such as Bcl-2 and p53 (Mehta et al. 1997). Bufalin, an active principal of Chinese medicine Chan-su has been shown to induce cell death of human leukemia U937 by apoptosis (Watabe et al. 1997). All fifteen tanshinone analogues isolated from the chloroform extract of Danshen roots (Salviae Miltiorrhizae Radix) have showed certain degrees of cytotoxicity to the KB, Hela, Colo-205 and Hep-2 carcinoma cell lines (Wang et al. 1996).
Nuclear Receptor Coactivators: Mechanism and Therapeutic Targeting in Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Andrew Cannon, Christopher Thompson, Rakesh Bhatia, Sushil Kumar
Because of the critical roles that they play in the development and progression of cancer, nuclear receptor coactivators represent therapeutic targets in cancer. In reality, the targeting of the nuclear receptor coactivators is difficult due to a high degree of conservation of domains involved in the interactions with nuclear receptors. Nonetheless, cardiac glycoside drugs were shown to cause decreased expression of NCOA1 and NCOA3 [143]. Of these, the cardiac glycoside bufalin was shown to be the most potent 137, miRNA-217, miRNA-17 and -20b, miRNA-485-3p and miRNA-485-5p among others have all been shown to target nuclear receptor coactivators with some therapeutic potential. While these represent relatively specific targeting mechanism, it remains difficult to translate the use of miRNAs as therapeutic strategies into the clinical setting [109, 146, 147]. In contrast to cardiac glycosides which downregulate the expression of NCOA1 and NCOA3, gossypol was shown to directly interact with the NR-box of the NCOA3 and inhibit the downstream transcriptional activation of NCOA3. Additionally, treatment with gossypol decreases the cellular concentrations of both NCOA1 and NCOA3 [148]. In contrast to targeting the expression and interaction domains of NCOAs, it is also possible to target the signaling pathways leading to activation of NR coactivators through various PTMs. In a study by Oh et al., it was shown that phosphorylation of Y1357 was essential to the functioning of NCOA3. Importantly, the authors showed that the phosphorylation of this residue was mediated by the tyrosine kinase c-Abl and thus the activation of NCOA3 in terms of downstream transcriptional activation was abrogated to a great extent by treatment with imatinib [149]. Finally, a recent report used a combinatorial peptide phage display-based approach to identify peptides that are able to bind specific nuclear receptor coactivator interaction surfaces. This study went on to demonstrate that several of these peptides were able to inhibit the transcriptional activation downstream of nuclear receptor coactivators that interact with androgen receptor. This approach presents a major advantage in the sense that the targeting of specific coactivator domains would represent a means by which interactions with a nuclear receptor could be disturbed regardless of the nuclear receptor coactivator involved. However, this approach lacks specificity as targeting a highly conserved interaction domain would likely disrupt many pathways potentially involving many coactivator and nuclear receptors [150]. Additionally, the use of peptides in the clinical setting remains a difficult task. inhibitor of NCOA expression. Importantly, treatment of xenograft breast cancer model with nanoformulated bufalin inhibited tumor growth. Like bufalin, gambogic acid (GA) was also shown to cause decreased expression of NCOA3 in non-hodgkin lymphoma and chronic myelogenous leukemia cells. Further, GA treatment caused cell cycle arrest and increased apoptotic rate [144, 145]. However, these studies only associate the mechanism of GA with decreases in NCOA3 expression and thus the mechanism of action remains to be confirmed. Similarly, several miRNAs including miRNA
mPEG-Cholic acid/TPGS mixed micelles for combined delivery of paclitaxel and bufalin to treat hepatocellular carcinoma
Published in Pharmaceutical Development and Technology, 2022
Yujia Liu, Xiaoyu Lu, Zhenhai Zhang, Shulong Jiang, Huixia Lv
Bufalin (BF) is the major active ingredient of toad venom, a traditional Chinese medicine, which has detoxification, analgesic, resuscitation, heart-strengthening and anti-tumor effects (Zhang et al. 2012). In-depth studies recently have pointed out that bufalin could affect the occurrence and development of various malignant tumors, including breast cancer, liver cancer, colon cancer and ovarian cancer (Qi et al. 2011; Chen et al. 2020; Zhan et al. 2020). In vitro studies showed that after incubation with 100 nM BF, 35.6% apoptosis of HepG2 cells was induced (Miao et al. 2013). However, BF is rarely used alone in vivo because of its high systemic toxicity. The anti-tumor mechanism of bufalin is mainly reflected in inhibiting cell proliferation (Jiang et al. 2010), promoting cell apoptosis (Miao et al. 2013), inducing cell differentiation (Numazawa et al. 1994), blocking cell cycle (Yu et al. 2018), inhibiting tumor angiogenesis (Xu et al. 2021), and regulating the body's immune system (Yang et al. 2018). Moreover, recent research has also found bufalin had the effect of reversing P-gp-mediated multidrug resistance, thereby improving the therapeutic effect of drug resistance in colon cancer (Yuan et al. 2017; 2018).
Neuroprotective and tumoricidal activities of cardiac glycosides. Could oleandrin be a new weapon against stroke and glioblastoma?
Published in International Journal of Neuroscience, 2018
İlhan Elmaci, Ebru Emekli Alturfan, Salih Cengiz, Aysel Ozpinar, Meric A. Altinoz
Bufalin derived from the toad skin has been used for several hundred years in traditional Chinese medicine to treat malignant diseases such as hepatocellular and hematologic cancers [7]. Leukemia cells execute apoptosis when treated with bufalin and oleandrin, but normal leukocytes do not, which suggest a specific therapeutic effect of CTS on tumor growth; and it is also generally suggested that hydrophobic CTS such as bufalin and oleandrin exert greater anticancer efficacy [7]. Indeed, an endogenous bufalin-like factor in human blood induces differentiation of leukemia cells [34]. A study involving more than 9000 patients revealed an inverse correlation between the plasma levels of digitoxin and the risk of leukemia, lymphoma, renal cancer and tumors of the urinary tract [35]. In a Phase II study conducted on 47 Stage IV melanoma patients, the addition of digoxin to an immunochemotherapy protocol including cisplatin, vinblastine, as well as the cytokines IL-2 and interferon (IFN) α2b, increased the global response rate from 19.5% (as observed in a parallel Phase III study involving 200 patients) to 55.3% [31].
Bufalin Suppresses Migration and Invasion of Hepatocellular Carcinoma Cells Elicited by Poly (I:C) Therapy
Published in OncoImmunology, 2018
Yinglu Feng, Yongan Chen, Yongbin Meng, Qingxin Cao, Qun Liu, Changquan Ling, Chen Wang
In ancient China, the skin of toad has been used in the prescription for treatment of cancer including HCC.34-37 Bufalin has been recognized as a prominent digoxin-like component of the Chinese medicine Chansu (venom of toad skin).38 Previous studies have demonstrated that bufalin exerts antitumor activities in various cancer cells by inhibiting proliferation, inducing apoptosis and cell cycle arrest, reversing drug resistance, modulating immune response and inhibiting invasion and metastasis of HCC.34,39-44 When investigating the effects of TLR3 triggering on HCC metastasis, we unexpectedly found that poly (I:C) could promote the migration and invasion of HCC cells. So we further explored whether bufalin could reverse the poly (I:C)-evoked metastasis of HCC while synergize with poly (I:C) in inducing apoptosis and inhibiting cell proliferation. We found that bufalin could inhibit poly (I:C)-inspired migration and invasion of HCC cells in vitro and the metastasis of HCC xenografts in vivo although synergistic effects of bufalin and poly (I:C) were not observed regarding proliferation and apoptosis of HCC. Our study suggests that bufalin could be used in combination with TLR3 agonists for the treatment of HCC for the sake of inhibiting metastasis of HCC.