Anti-HIV drugs for cancer therapeutics: back to the future?

Chow, Warren; Jiang, Chunling; Guan, Min

doi:10.1016/s1470-2045(08)70334-6

Cited by 171 publications

(164 citation statements)

References 71 publications

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“…NFR ability to trigger eEF2K signaling was comparable in all human and mouse cell types tested, indicating that this pathway is a conserved hallmark of NFR-mediated stress response. It is therefore reasonable to predict that this response could be part of the NFR anti-tumoral effects observed in cancer patients [10][11][12]. The activation of eEF2K is part of an adaptation program that may help stressed cells, such as cancer cells, to cope with conditions of low nutriment and energy [38].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

et al. 2016

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Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes including cancer progression. Here we show that inhibitors of the HIV aspartyl protease (HIV-PIs), nelfinavir in particular, trigger a robust activation of eEF2K leading to the phosphorylation of eEF2. Beyond its anti-viral effects, nelfinavir has antitumoral activity and promotes cell death. We show that nelfinavir-resistant cells specifically evade eEF2 inhibition. Decreased cell viability induced by nelfinavir is impaired in cells lacking eEF2K. Moreover, nelfinavir-mediated anti-tumoral activity is severely compromised in eEF2K-deficient engrafted tumors in vivo. Our findings imply that exacerbated activation of eEF2K is detrimental for tumor survival and describe a mechanism explaining the anti-tumoral properties of HIV-PIs.

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Section: Discussionmentioning

confidence: 99%

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

et al. 2016

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“…The HIV-PIs were among the first drugs to reach the clinic that were developed with computer technology applied to compound design based on the X-ray structures. Although these drugs were designed to specifically inhibit the HIV aspartyl protease, they display a wide range of activities independently of their ability to target HIV (17,18). Clinical trials are underway to evaluate the effectiveness of HIV-PIs on suppressing tumor progression…”

Section: Ppp1r15bmentioning

confidence: 99%

“…Nelfinavir has been used for years to treat HIV; its repositioning in diseases that would benefit from decreased translation speed could therefore be of interest. (17,19). It was proposed that ER stress contributes to their antineoplastic activity (20)(21)(22).…”

Section: Significancementioning

confidence: 99%

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Gassart

Bujisic

Zaffalon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses.

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“…Lopinavir-NO deserves additional studies for its possible use in T-cell-mediated autoimmune diseases including, but not limited to autoimmune hepatitis. Antiretroviral protease inhibitors (PIs) in combination with nucleoside or non-nucleoside reverse transcriptase inhibitors are the basis for the highly active antiretroviral therapy (HA-ART) that is efficient in suppression of HIV replication and reduction of clinical manifestations of the disease [1].In addition to their primary pharmacological indication, these drugs have also been described to possess antineoplastic and immunomodulatory properties both in in vitro and in vivo pre-clinical settings [2][3][4].However, serious side effects including dyslipidaemia, insulin resistance, lipodystrophy, hepatotoxicity and atherosclerotic cardiovascular complications [5][6][7][8][9] have dampened the possible extension of these drugs to therapeutic areas different than HIV infection.It has been previously demonstrated that nitric oxide (NO)-hybridization may reduce toxicity of parental compounds while enhancing the pharmacological potency of the drugs [10]. Along this line of research, several derivatives of PIs have been synthesized at OncoNOx (Copenhagen, Denmark) by covalent attachment of NO moiety to the parental molecules.…”

mentioning

confidence: 99%

“…In addition to their primary pharmacological indication, these drugs have also been described to possess antineoplastic and immunomodulatory properties both in in vitro and in vivo pre-clinical settings [2][3][4].…”

mentioning

confidence: 99%

Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir

Fagone

Mangano

Quattrocchi

et al. 2015

Basic Clin Pharmacol Toxicol

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HIV protease inhibitors (PIs) are antiretroviral agents, which have been found to also affect several cellular processes, such as inflammation and cell progression. In studies on non-steroidal, anti-inflammatory drugs, the addition of a nitric oxide (NO) moiety has been shown to both reduce their toxicity and enhance their pharmacological efficacy. Along this line of research, several derivatives of PIs have been synthesized by covalent attachment of NO moiety to the parental molecules. Previous work has indicated that NO-hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir-NO that while retaining the antiretroviral effect, acquires antitumoural and immunomodulatory properties along with reduced toxicity in vitro and in vivo. These data prompted us to evaluate the effects of NO-hybridization on two other PIs, Lopinavir and Ritonavir. The two NO-derivatives were compared head to head with their parental compounds on human primary peripheral blood mononuclear cells as well as on human primary macrophages. Lopinavir-NO and Lopinavir were also screened in an in vivo model of autoimmune hepatitis. Our results prove that Lopinavir-NO exerts markedly superior effects as compared to the parental compound both in vitro and in vivo. On the contrary, Ritonavir-NO effects overlapped those of Ritonavir. These data demonstrate that NO-hybridization of Lopinavir generates a derivative with significantly stronger immunomodulatory effects that are apparently related to an action of the compound on T-cell secretory capacity. Lopinavir-NO deserves additional studies for its possible use in T-cell-mediated autoimmune diseases including, but not limited to autoimmune hepatitis. Antiretroviral protease inhibitors (PIs) in combination with nucleoside or non-nucleoside reverse transcriptase inhibitors are the basis for the highly active antiretroviral therapy (HA-ART) that is efficient in suppression of HIV replication and reduction of clinical manifestations of the disease [1].In addition to their primary pharmacological indication, these drugs have also been described to possess antineoplastic and immunomodulatory properties both in in vitro and in vivo pre-clinical settings [2][3][4].However, serious side effects including dyslipidaemia, insulin resistance, lipodystrophy, hepatotoxicity and atherosclerotic cardiovascular complications [5][6][7][8][9] have dampened the possible extension of these drugs to therapeutic areas different than HIV infection.It has been previously demonstrated that nitric oxide (NO)-hybridization may reduce toxicity of parental compounds while enhancing the pharmacological potency of the drugs [10]. Along this line of research, several derivatives of PIs have been synthesized at OncoNOx (Copenhagen, Denmark) by covalent attachment of NO moiety to the parental molecules.Previous work carried out by ourselves and others has indicated that NO-hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir-NO that while retaining the antiretro...

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Anti-HIV drugs for cancer therapeutics: back to the future?

Cited by 171 publications

References 71 publications

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir

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