Plasmodium falciparum is a unicellular protozoan parasite and causative agent of a severe form of malaria in humans, accounting for very high worldwide fatality rates. At the molecular level, survival of the parasite within the human host is mediated by P. falciparum heat shock proteins (PfHsps) that provide protection during febrile episodes. The ATP-dependent chaperone activity of Hsp70 relies on the co-chaperone J domain protein (JDP), with which it forms a chaperone-co-chaperone complex. The exported P. falciparum JDP (PfJDP), PFA0660w, has been shown to stimulate the ATPase activity of the exported chaperone, PfHsp70-x. Furthermore, PFA0660w has been shown to associate with another exported PfJDP, PFE0055c, and PfHsp70-x in J-dots, highly mobile structures found in the infected erythrocyte cytosol. Therefore, the present study aims to conduct a structural and functional characterization of the full-length exported PfJDP, PFE0055c. Recombinant PFE0055c was successfully expressed and purified and found to stimulate the basal ATPase activity of PfHsp70-x to a greater extent than PFA0660w but, like PFA0660w, did not significantly stimulate the basal ATPase activity of human Hsp70. Small-molecule inhibition assays were conducted to determine the effect of known inhibitors of JDPs (chalcone, C86) and Hsp70 (benzothiazole rhodacyanines, JG231 and JG98) on the basal and PFE0055c-stimulated ATPase activity of PfHsp70-x. In this study, JG231 and JG98 were found to inhibit both the basal and PFE0055c-stimulated ATPase activity of PfHsp70-x. C86 only inhibited the PFE0055c-stimulated ATPase activity of PfHsp70-x, consistent with PFE0055c binding to PfHsp70-x through its J domain. This research has provided further insight into the molecular basis of the interaction between these exported plasmodial chaperones, which could inform future antimalarial drug discovery studies.

2019-12-01·Life Sciences3区 · 医学

Molecular mechanisms of curcumin and its analogs in colon cancer prevention and treatment

3区 · 医学

Review

作者: Selvam, Chelliah ; Purushothaman, Yasodha ; Hosseini Zare, Maryam Sadat ; Prabu, Sakthivel Lakshmana ; Jordan, Brian C ; Umamaheswari, Appavoo ; Thilagavathi, Ramasamy

Colorectal cancer remains to be the most prevalent malignancy in humans and 1.5 million men and women living in the United States are diagnosed with colorectal cancer, with a predicted 145,600 new cases to be diagnosed in 2019. Curcuminoids and its synthetic analogs are now of interest due to their bioactive attributes, especially their action as anticancer activity in various cancer cell line models. Several in vivo and in vitro studies have substantially proved their anticancer activities against colon cancer cell lines. Curcumin analogues like IND-4, FLLL, GO-Y030 and C086 have demonstrated to produce greater cytotoxicity when experimentally studied and study results from many have been suggested to be the same. Combination of curcumin with therapeutic cancer agents like tolfenamic acid, 5-fluorouracil, resveratrol and dasatinib showed improved cytotoxicity and chemotherapeutic effect. The results propose that employment of curcumin with novel drug delivery systems like liposome, micelles and nanoparticle have been performed which could improve the therapeutic efficacy against colon cancer. The present review highlights the mechanism of action, synergistic effect and novel delivery methods to improve the therapeutic potential of curcumin.

2018-07-15·Cancer Research1区 · 医学

Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer

1区 · 医学

Article

作者: Kim, Yeong Sang ; Beebe, Kristin E. ; Shao, Hao ; Rivera-Marquez, Genesis M. ; Moses, Michael A. ; Gestwicki, Jason E. ; Watson, Matthew J. ; Wells, Catherine ; Zuehlke, Abbey D. ; Kumar, Vineet ; Neckers, Leonard M. ; Lee, Sunmin ; Trepel, Jane B. ; Malhotra, Sanjay V. ; Weigel, Nancy L. ; Bingman, William E. ; Oshima, Nobu

AbstractCastration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. In vivo, Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy.Significance:These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy. Cancer Res; 78(14); 4022–35. ©2018 AACR.

100 项与 C-086 相关的药物交易

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