New study below [1].
This is a cell study, but it provides a rationale for using Metformin with Abiraterone/Enzalutamide, i.e. androgen receptor-axis-rargeted (ARAT) agents.
"The finding that patients with diabetes taking metformin, but not other anti-diabetic drugs, have a decreased risk of dying from PC led to extensive studies on the anti-tumor effects of metformin in PC."
"Normally PARP-1 is involved in the repair of DNA damage induced by a variety of cellular stresses. However, additional functions of PARP-1 have also been revealed"
"PARP-1 can be cleaved by several ‘suicidal’ proteases. The cleaved PARP-1 fragment containing a DNA binding domain can still bind to DNA but cannot catalyze DNA repair as it lacks the catalytic domain. Thus, the cleaved PARP-1 fragment that binds DNA can act as a dominant-negative inhibitor of PARP-1, inhibiting DNA repair and leading to cell death."
"Excessive activation of PARP-1 can also lead to ... parthanatos" (aka PARP-1 dependent cell death)
"In this paper, we used two human androgen-sensitive PC cell lines, LNCaP and VCaP, to study the role of metformin and ARATs in prostate cancer. We report that in PC cells, metformin, in combination with an inhibitor of androgen biosynthesis (Abi) or an AR targeting agent (Enz), can mediate PARP-1-dependent PCD: a) via enhanced PARP-1 cleavage that is essentially independent of caspase 3 activation, b) via enhanced PARP-1 activation, and c) at lower concentrations than have been observed with metformin in prior studies. This report expands the possible pathways by which metformin-based and ARAT-based targeting strategies could potentially be further developed and enhanced to treat PC."
"ADT induces initial responses in the majority of patients by disrupting androgen receptor (AR)-axis signaling. However, the disease eventually progresses within two years of ADT in most patients despite castrate levels of serum testosterone, resulting in castration resistant prostate cancer (CRPC). Such progression is often due to the restoration of androgen-AR signaling under androgen deprived conditions. Therefore, agents targeting either androgen biosynthesis (e.g., abiraterone acetate (Abi)) or AR signaling (e.g., enzalutamide (Enz)), i.e., the so-called androgen receptor-axis-targeted (ARAT) agents, were introduced as a second line therapy in patients with CRPC. While both Abi and Enz can improve overall survival among responding men, these treatments also eventually fail, resulting in disease progression. Further, other men with CRPC may be resistant to Abi or Enz de novo. Studies suggest that resistance to Enz and Abi may in part be due to altered expression of AR and/or AR splice variants in PC cells."
"Consistent with prior studies, ... treatment with Abi (5 µM) or Enz (10 µM) for 5 days results in an approximately 1.5-fold increase in AR expression in LNCaP cells ... In contrast to LNCaP cells, VCaP cells express both AR and ARv7 ... Enz or Abi treatment for 5 days primarily increased protein levels of ARv7 in the VCaP cells".
"We evaluated the effects of metformin on LNCaP and VCaP cells. Metformin inhibited LNCaP and VCaP cell proliferation ... Inhibition was first observed at the 1 mM metformin dose, which resulted in approximately 20–30% inhibition in both cell lines. At metformin concentrations >1 mM, inhibition of PC cell proliferation occurred in a dose dependent manner".
"... metformin and ARATs together had an additive to synergistic anti-proliferative effect"
"We found ARATs enhanced cleavage of PARP-1 in VCaP but not LNCaP cells. However, metformin (1 µM) as a single agent induced PARP-1 cleavage in both cell lines within 4–5 days of treatment. Metformin in combination with ARATs is particularly effective in inducing cleavage of PARP-1"
"Many of the initial trials with metformin in PC have evaluated it in the advanced castration resistant setting, a disease state that is generally more refractory to additional therapies compared to castration sensitive disease. Given that metformin enhances the anti-cellular effects of ARATs in androgen-responsive cells, it will be of interest to evaluate prospectively metformin/ARAT-based combinations, particularly in treatment-naïve, castration-sensitive settings of PC. Indeed, large retrospective analysis has demonstrated that diabetic PC patients initiated on ADT who are on metformin have statistically significant better overall and cancer specific survival compared to diabetic PC patients on ADT but not metformin".
-Patrick
[1] Full text: mdpi.com/2072-6694/13/4/633...
Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells
by Yi Xie 1,*,†OrcID, Linbo Wang 1, Mohammad A. Khan 1, Anne W. Hamburger 1,2, Wei Guang 1, Antonino Passaniti 1,2,3, Kashif Munir 4,5OrcID, Douglas D. Ross 1,2,3,5, Michael Dean 6OrcID and Arif Hussain 1,2,3,5,7,*
1
Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA
2
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
3
Baltimore VA Medical Center, Baltimore, MD 21201, USA
4
Division of Endocrinology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
5
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
6
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
7
Department of Molecular Biology and Biochemistry, University of Maryland School of Medicine, Baltimore, MD 21210, USA
*
Authors to whom correspondence should be addressed.
†
Current address: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Academic Editor: Anderson Joseph Ryan
Cancers 2021, 13(4), 633; doi.org/10.3390/cancers1304...
Received: 2 January 2021 / Revised: 20 January 2021 / Accepted: 29 January 2021 / Published: 5 February 2021
(This article belongs to the Special Issue PARPs in Cancer)
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Simple Summary
In the present study, we sought to determine whether a commonly used oral drug to treat adult-onset diabetes, metformin, which has a longstanding clinical history and known safety and tolerability profile, can improve the anti-cancer effects of two well-established oral agents currently in use to treat advanced prostate cancer, abiraterone and enzalutamide. We used androgen-sensitive cell culture models of human prostate cancer to test our hypothesis. We found that metformin and the oral anti-prostate cancer agents together are more effective in inhibiting prostate cancer cell growth and inducing prostate cancer cell death than when used alone. We identified new pathways by which the enhanced anti-cancer effects occur with the combination treatments. The present work suggests that incorporating metformin with abiraterone or enzalutamide may improve treatment outcomes in hormone sensitive prostate cancer.
Abstract
We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC.
Keywords: prostate cancer; metformin; ARAT; PARP-1; poly(ADP-ribose) (PAR); lysosome
Study reports direct targets of ivermectin in prostate cancer
My dad 65 has stage 4 prostate cancer (HELP)
