HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition

Selvendiran, Karuppaiyah; Ahmed, Shabnam; Dayton, Alex; Kuppusamy, M. Lakshmi; Rivera, Brian K.; Kálai, Tamás; Hideg, Kálmán; Kuppusamy, Periannan

doi:10.4161/cbt.12.9.17713

Cited by 61 publications

(54 citation statements)

References 45 publications

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“…This is in contrast to platinum-based chemotherapeutic agents, which promote ROS accumulation in both cancer and normal cells, leading to significant systemic toxicity. A previous study found that mice cotreated with cisplatin and HO-3867 did not have a reduction in body weight compared with control, whereas those treated with the same dose of cisplatin alone did lose weight during treatment (27). Given these findings it is possible that combining cisplatin with HO-3867 may protect against cisplatin-associated nephrotoxicity.…”

Section: Discussionmentioning

confidence: 99%

HO-3867, a Safe STAT3 Inhibitor, Is Selectively Cytotoxic to Ovarian Cancer

et al. 2014

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STAT3 is well corroborated preclinically as a cancer therapeutic target, but tractable translational strategies for its blockade by small molecule inhibitors have remained elusive. In this study, we report the development of a novel class of bifunctional STAT3 inhibitors, based on conjugation of a diarylidenyl-piperidone (DAP) backbone to an N-hydroxypyrroline (−NOH) group, which exhibits minimal toxicity against normal cells and good oral bioavailability. Molecular modeling studies of this class suggested direct interaction with the STAT3 DNA binding domain. In particular, the DAP compound HO-3867 selectively inhibited STAT3 phosphorylation, transcription, and DNA binding without affecting the expression of other active STATs. HO-3867 exhibited minimal toxicity toward noncancerous cells and tissues but induced apoptosis in ovarian cancer cells. Pharmacologic analysis revealed greater bioabsorption and bioavailability of the active (cytotoxic) metabolites in cancer cells compared with normal cells. The selective cytotoxicity of HO-3867 seemed to be multifaceted, eliciting differential activation of the Akt pathway in normal versus cancer cells. RNAi attenuation experiments confirmed the requirement of STAT3 for HO-3867–mediated apoptosis in ovarian cancer cells. In vivo testing showed that HO-3867 could block xenograft tumor growth without toxic side effects. Furthermore, in primary human ovarian cancer cells isolated from patient ascites, HO-3867 inhibited cell migration/invasion and survival. Our results offer preclinical proof-of-concept for HO-3867 as a selective STAT3 inhibitor to treat ovarian cancer and other solid tumors where STAT3 is widely upregulated.

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Section: Discussionmentioning

confidence: 99%

HO-3867, a Safe STAT3 Inhibitor, Is Selectively Cytotoxic to Ovarian Cancer

et al. 2014

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“…16 It is a dual-acting molecule with targeted antiproliferative and antioxidant capabilities. 14 Its antiproliferative activity has been evaluated using a number of cancer cell lines, 14 murine xenograft tumors, 17,33,34 serum-stimulated SMCs, 15 and balloon injury-mediated carotid artery restenosis in rats. 15 The compound, usually administered as a dietary supplement, is readily bio-absorbed and retained in tissues for 24 hours.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Hypertension Secondary to Left-Heart Failure Involves Peroxynitrite-Induced Downregulation of PTEN in the Lung

et al. 2013

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Pulmonary hypertension (PH) that occurs after left-heart failure (LHF), classified as Group 2 PH, involves progressive pulmonary vascular remodeling induced by smooth muscle cell (SMC) proliferation. However, mechanisms involved in the activation of SMCs remain unknown. The objective of this study was to determine the involvement of peroxynitrite and phosphatase-and-tensin homolog on chromosome 10 (PTEN) in vascular SMC proliferation and remodeling in the LHF-induced PH (LHF-PH). LHF was induced by permanent ligation of left anterior descending coronary artery in rats for 4 weeks. MRI, ultrasound, and hemodynamic measurements were performed to confirm LHF and PH. Histopathology, western blot, and real-time polymerase chain reaction analyses were used to identify key molecular signatures. Therapeutic intervention was demonstrated using an antiproliferative compound, HO-3867. LHF-PH was confirmed by significant elevation of mean pulmonary artery pressure (mean pulmonary artery pressure/mm Hg: 35.9±1.8 versus 14.8±2.0, control; P<0.001) and vascular remodeling. HO-3867 treatment decreased mean pulmonary artery pressure to 22.6±0.8 mm Hg (P<0.001). Substantially higher levels of peroxynitrite and significant loss of PTEN expression were observed in the lungs of LHF rats when compared with control. In vitro studies using human pulmonary artery SMCs implicated peroxynitrite-mediated downregulation of PTEN expression as a key mechanism of SMC proliferation. The results further established that HO-3867 attenuated LHF-PH by decreasing oxidative stress and increasing PTEN expression in the lung. In conclusion, peroxynitrite and peroxynitrite-mediated PTEN inactivation seem to be key mediators of lung microvascular remodeling associated with PH secondary to LHF.

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“…29,30 HO-3867 inhibits STAT3 and STAT3-regulated anti-apoptotic genes such as Bcl-2 and Bcl-X L , contributing to decreased cancer cell survival via induction of apoptosis. Previous studies have shown that members of the Bcl-2 family play a key role in regulating caspase activation during apoptosis 31 and that Bcl-2 and Bcl-x L are negative regulators of caspase activation.…”

Section: Discussionmentioning

confidence: 99%