Immune regulation of therapy-resistant niches: emerging targets for improving anticancer drug responses

Jinushi, Masahisa

doi:10.1007/s10555-014-9501-9

Cited by 10 publications

(4 citation statements)

References 94 publications

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“…The tumor cell is ultimately destroyed by direct cell-mediated cytotoxicity, as well as an indirect antibody complement-mediated cytotoxicity (53). However, the majority of tumors have been demonstrated to lose the expression of MHC molecules, resulting in the loss of presenting tumor antigens, thus evading T-cell recognition (40,53). In addition, when the balance of the immune checkpoint was destroyed, certain tumors upregulated inhibitory molecules to evade the immune response (40).…”

Section: Regulating the Immunomodulatory Activitiesmentioning

confidence: 99%

“…However, the majority of tumors have been demonstrated to lose the expression of MHC molecules, resulting in the loss of presenting tumor antigens, thus evading T-cell recognition (40,53). In addition, when the balance of the immune checkpoint was destroyed, certain tumors upregulated inhibitory molecules to evade the immune response (40). Due to the strong heterogeneity of cancer, exploring novel effective drug targets and therapeutic strategies to overcome the problem is required.…”

Section: Regulating the Immunomodulatory Activitiesmentioning

confidence: 99%

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Efficacy of traditional Chinese medicine in treating cancer

et al. 2015

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Section: Regulating the Immunomodulatory Activitiesmentioning

confidence: 99%

Section: Regulating the Immunomodulatory Activitiesmentioning

confidence: 99%

Efficacy of traditional Chinese medicine in treating cancer

et al. 2015

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“…GPCRs are the largest family of integral membrane proteins comprising seven conserved transmembrane helices, three extracellular loops, and three intracellular loops. GPCRs are involved in many diseases and disorders [204][205][206][207][208] and are sought-after drug targets. Approximately 34% of all US Food and Drug Administration (FDA) approved drugs target GPCRs.…”

Section: Gpcrsmentioning

confidence: 99%

Rational design of allosteric modulators: Challenges and successes

Chatzigoulas

Cournia

2021

WIREs Comput Mol Sci

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Recent advances in structural biology and computational techniques have revealed allosteric mechanisms for an abundance of targets leading to the establishment of rational design of allosteric modulators as a new avenue for drug discovery. Considering that allostery is an intrinsic property of the protein conformational ensemble, allosteric drug design has the potential to develop into an innovative approach to modulate the dysregulation of therapeutic targets that are considered to be undruggable at their orthosteric site, explore strategic design opportunities to tackle new chemical space, or develop mutant-specific therapies to target mutations occurring far from the enzyme active site. Traditionally, allosteric drug discovery has been performed through high-throughput screening or through serendipitous discoveries; however, recent developments in structure-based and ligand-based methods have led to exciting advancements of designing bioactive allosteric ligands rationally. In this review article, we highlight the advantages and disadvantages of allosteric modulators and present structure-based and ligand-based drug design methodologies for the identification of allosteric binding sites and allosteric modulators. We also illustrate representative studies for allosteric modulators design for proteins belonging to a wide range of protein families, also considering irreversible binding with covalent allosteric modulators. Additionally, we analyze challenges and successes in the rational design of allosteric inhibitors and activators. Finally, we present the future of rational allosteric ligand design with newly built computational tools that we expect to be applied in future studies, concluding to theoretical and practical guidelines for allosteric ligand design strategies and identify knowledge gaps that need to be addressed to improve efficiency in allosteric drug design.

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“…Interestingly, increasing number of studies report that cytotoxic anticancer drugs, including Cis, besides promoting apoptosis [3,4,80], may act as modulators of immunological activity [81][82][83][84]. Moreover, carbon nanostructures are reported to possess immunomodulatory activity as well [25].…”

Section: Antitumor Action In Vivomentioning

confidence: 99%

C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

et al. 2016

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A novel nano-formulation of the anticancer drug cisplatin (Cis) with C 60 fullerene (C 60 +Cis complex) was developed, demonstrating enhanced cytotoxic activity towards tumor cell lines in vitro n comparison to Cis alone. The enhanced proapoptotic activity of the novel complexes was found to be tightly connected with their unique capability to circumvent cancer drug resistance in vitro, as revealed by investigation of human leukemia cells HL-60 together with their sublines resistant towards doxorubicin (HL-60/adr, multidrug resistance protein-1=MRP-1=ABCC1 overexpressing) and vincristine (HL-60/vinc, P-glycoprotein=P-gp=ABCB1 overexpressing). The enhanced anticancer activity of the developed С 60 +Cis complexes was also confirmed in vivo on male C57BL/6J mice bearing Lewis lung carcinoma, effectively inhibiting tumor growth and formation of metastases in comparison to free single Cis. For better understanding of molecular mechanisms underlying the potential ability of the С 60 +Cis complexes to circumvent cancer drug resistance, a molecular docking study was conducted. This analysis demonstrated the potential capability of C 60 fullerene to form van der Waals interactions with potential binding sites of P-gp, MRP-1and MRP-2 (ABCC2) molecules, with maximum affinity to MRP-2. The observed phenomenon might indicate the mechanism how the C 60 +Cis complex bypasses drug resistance of cancer cells by direct binding to ABC transporter proteins. Additionally, the results of Ames mutagenicity test demonstrated that immobilization of Cis on С 60 fullerene significantly diminishes mutagenic activity of Cis and may reduce the probability of secondary neoplasms induction. Concluding, the synthesized C 60 +Cis complex effectively induces cancer cell death in vitro and inhibits tumor growth in vivo, circumventing cancer cell resistance to chemotherapy due to the specific affinity of C 60 fullerene towards ABC-transporter proteins. The obtained results indicate the C 60 +Cis complex as a promising novel chemotherapeutic agentespecially for treatment of drug-resistant tumors.

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Immune regulation of therapy-resistant niches: emerging targets for improving anticancer drug responses

Cited by 10 publications

References 94 publications

Efficacy of traditional Chinese medicine in treating cancer

Efficacy of traditional Chinese medicine in treating cancer

Rational design of allosteric modulators: Challenges and successes

C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

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