Two Targets, One Hit: new Anticancer Therapeutics to Prevent Tumorigenesis Without Cardiotoxicity

A serious adverse effect of cancer therapies is cardiovascular toxicity, which significantly limits the widespread use of antineoplastic agents. The promising new field of cardio-oncology offers the identification of potent anti-cancer therapeutics that effectively inhibit cancer cell proliferation without causing cardiotoxicity. Future introduction of recently identified cardio-safe compounds into clinical practice (including ERK dimerization inhibitors or BAX allosteric inhibitors) is expected to help oncologists avoid unwanted cardiological complications associated with therapeutic interventions.

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Clinical significance of activated Wnt/β-catenin signaling in apoptosis inhibition of oral cancer

Open Life Sciences ◽

10.1515/biol-2021-0104 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1045-1052

Author(s):

Yufeng Wang ◽

Zheng Cao ◽

Fengjia Liu ◽

Yuejian Ou

Keyword(s):

Cell Proliferation ◽

Signaling Pathway ◽

Apoptotic Cell ◽

Cancer Cell Proliferation ◽

Rt Pcr ◽

Sirna Transfection ◽

Apoptosis Resistance ◽

Apoptosis Inhibition ◽

Anti Cancer ◽

Evolutionarily Conserved

Abstract Wnt/β‐catenin signaling is an evolutionarily conserved pathway and plays a crucial role in regulating cancer cell proliferation and tumorigenesis. However, the molecular mechanism behind the Wnt/β‐catenin signaling-mediated carcinogenesis and apoptosis resistance in oral squamous cell carcinoma is not well characterized so far. In the present study, we have investigated the effect of β‐catenin depletion of the perversely activated Wnt/β-catenin signaling pathway on apoptosis resistance and tumorigenesis of the human OSCC cell line SCC-55. RT-PCR and western blot analysis demonstrated that the Wnt/β-catenin signaling pathway and its downstream targets such as DKK1 and AXIN2 are aberrantly activated in SCC-55 cells. Furthermore, upon silencing (RNA interference) of β‐catenin in SCC-55, cells became more sensitive toward the chemotherapeutic drugs and thus resulted in apoptotic cell death. Meanwhile, flow cytometry analysis confirmed the enhanced apoptosis and activation of caspases in β‐catenin RNAi cells. Besides ensuing β-catenin–siRNA transfection, the cell proliferation and cancer colony generating efficiencies are significantly impeded compared to the non-transfected cells. Furthermore, the tumorigenicity was inhibited by the downregulation of OCT-4 in β‐catenin-silenced SCC-55 cells. Altogether, Wnt/β‐catenin signaling could potentially target anti-cancer drugs to induce apoptosis and achieve a better clinical outcome.

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Breast Cancer Therapeutics Based on Fusarochromanone and EGFR Inhibitors

10.21203/rs.3.rs-289662/v1 ◽

2021 ◽

Author(s):

Natalie Carroll ◽

Alena Smith ◽

Brian A. Salvatore ◽

Elahe Mahdavian

Keyword(s):

Breast Cancer ◽

Mode Of Action ◽

Cancer Therapeutics ◽

Egfr Inhibitors ◽

Cancer Therapies ◽

Racemic Form ◽

Combination Treatments ◽

Anti Cancer ◽

Cancer Agent ◽

Cancer Activity

Abstract Background: Fusarochromanone (FC101) is a small molecule with potent anti-cancer activity. It was originally derived from the fungal plant pathogen, Fusarium equiseti, and it has also been synthesized in non-racemic form in our lab. Numerous studies reveal the promising biological activity of FC101, including potent anti-angiogenic and anti-cancer activity. While FC101 is potent as a single drug treatment across many cancer cell lines, current cancer therapies often incorporate a combination of drugs in order to increase efficacy and decrease the development of drug resistance. In this study, we leverage drug combinations and cellular phenotypic screens to address important questions about FC101’s mode of action and its potential synergies as an anti-cancer therapeutic agent in triple negative breast cancer (TNBC).Method: We hypothesized that FC101’s activity against TNBC is similar to the known mTOR inhibitor, everolimus, because FC101 reduces the phosphorylation of two key mTOR substrates, S6K and S6. Since everolimus synergistically enhances the anti-cancer activities of known EGFR inhibitors (erlotinib or lapatinib) in TNBC, we performed analogous studies with FC101. Phenotypic cellular assays helped assess whether FC101 (in both single and combination treatments) acts similarly to everolimus.Results: FC101 outperformed all other single treatments in both cell proliferation and viability assays. Unlike everolimus, however, FC101 brought about a sustained decrease in cell viability in drug washout studies. None of the other drugs were able to maintain comparable effects upon removal of the treatment agents. Although we observed slightly additive effects when the TNBC cells were treated with FC101 and either EGFR inhibitor, those effects were not truly synergistic in the manner displayed with everolimus. Conclusion: Our results rule out direct inhibition of mTOR by FC101 and suggest that FC101 acts through a different mechanism than everolimus. This lays the foundation for the refinement of our hypothesis in order to better understand FC101’s mode of action as a novel anti-cancer agent.

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The Complex Cancer Care Coverage Environment — What is the Role of Legislation?

The Journal of Law Medicine & Ethics ◽

10.1177/1073110520958879 ◽

2020 ◽

Vol 48 (3) ◽

pp. 538-551 ◽

Cited By ~ 1

Author(s):

Christine Leopold ◽

Rebecca L. Haffajee ◽

Christine Y. Lu ◽

Anita K. Wagner

Keyword(s):

Cancer Care ◽

Insurance Coverage ◽

Cancer Therapeutics ◽

Health Insurance Coverage ◽

Cancer Therapies ◽

Cancer Treatments ◽

Difficult Situation ◽

Cell Therapies ◽

State Laws ◽

Anti Cancer

Over the past decades, anti-cancer treatments have evolved rapidly from cytotoxic chemotherapies to targeted therapies including oral targeted medications and injectable immunooncology and cell therapies. New anti-cancer medications come to markets at increasingly high prices, and health insurance coverage is crucial for patient access to these therapies. State laws are intended to facilitate insurance coverage of anti-cancer therapies.Using Massachusetts as a case study, we identified five current cancer coverage state laws and interviewed experts on their perceptions of the relevance of the laws and how well they meet the current needs of cancer care given rapid changes in therapies. Interviewees emphasized that cancer therapies, as compared to many other therapeutic areas, are unique because insurance legislation targets their coverage. They identified the oral chemotherapy parity law as contributing to increasing treatment costs in commercial insurance. For commercial insurers, coverage mandates combined with the realities of new cancer medications — including high prices and often limited evidence of efficacy at approval — compound a difficult situation. Respondents recommended policy approaches to address this challenging coverage environment, including the implementation of closed formularies, the use of cost-effectiveness studies to guide coverage decisions, and the application of value-based pricing concepts. Given the evolution of cancer therapeutics, it may be time to evaluate the benefits and challenges of cancer coverage mandates.

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The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention

Cancers ◽

10.3390/cancers11030427 ◽

2019 ◽

Vol 11 (3) ◽

pp. 427 ◽

Cited By ~ 20

Author(s):

Ranjini Sankaranarayanan ◽

Chaitanya Valiveti ◽

D. Kumar ◽

Severine Van slambrouck ◽

Siddharth Kesharwani ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cell Proliferation ◽

Cyclin Dependent Kinase ◽

Specific Amino Acid ◽

In Silico Studies ◽

Anti Cancer ◽

Anti Oxidant ◽

First Time ◽

Related Compounds

Flavonoids have emerged as promising compounds capable of preventing colorectal cancer (CRC) due to their anti-oxidant and anti-inflammatory properties. It is hypothesized that the metabolites of flavonoids are primarily responsible for the observed anti-cancer effects owing to the unstable nature of the parent compounds and their degradation by colonic microflora. In this study, we investigated the ability of one metabolite, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) to inhibit Cyclin Dependent Kinase (CDK) activity and cancer cell proliferation. Using in vitro kinase assays, we demonstrated that 2,4,6-THBA dose-dependently inhibited CDKs 1, 2 and 4 and in silico studies identified key amino acids involved in these interactions. Interestingly, no significant CDK inhibition was observed with the structurally related compounds 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) and phloroglucinol, suggesting that orientation of the functional groups and specific amino acid interactions may play a role in inhibition. We showed that cellular uptake of 2,4,6-THBA required the expression of functional SLC5A8, a monocarboxylic acid transporter. Consistent with this, in cells expressing functional SLC5A8, 2,4,6-THBA induced CDK inhibitory proteins p21Cip1 and p27Kip1 and inhibited cell proliferation. These findings, for the first time, suggest that the flavonoid metabolite 2,4,6-THBA may mediate its effects through a CDK- and SLC5A8-dependent pathway contributing to the prevention of CRC.

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Antioxidant Activities and Anti-Cancer Cell Proliferation Properties of Natsuhaze (Vaccinium oldhamii Miq.), Shashanbo (V. bracteatum Thunb.) and Blueberry Cultivars

Plants ◽

10.3390/plants2010057 ◽

2013 ◽

Vol 2 (1) ◽

pp. 57-71 ◽

Cited By ~ 11

Author(s):

Hirotoshi Tsuda ◽

Hisato Kunitake ◽

Ryoko Kawasaki-Takaki ◽

Kazuo Nishiyama ◽

Masao Yamasaki ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cell ◽

Antioxidant Activities ◽

Cancer Cell Proliferation ◽

Anti Cancer

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A Review of the Cardiovascular Effects of Oncology Agents

Journal of Pharmacy Practice ◽

10.1177/0897190008314776 ◽

2008 ◽

Vol 21 (2) ◽

pp. 146-158 ◽

Cited By ~ 5

Author(s):

Bradi L. Frei ◽

Scott A. Soefje

Keyword(s):

Heart Failure ◽

Cardiovascular Disease ◽

Adverse Effect ◽

Cancer Therapy ◽

Cardiovascular Effects ◽

Cancer Therapies ◽

Cardiovascular Toxicity ◽

Action Monitoring ◽

Increased Risk ◽

Chemotherapy Agents

Cardiovascular toxicity is an important adverse effect of several classes of oncology drugs. Because cancer survivors are living longer, the late effects of cancer therapy must be addressed. Many patients diagnosed with cancer are already at an increased risk for cardiovascular disease before drug treatment. Select chemotherapy agents further complicate the issue because of their own ability to induce cardiovascular toxicities or exacerbate preexisting conditions. Hypertension, dyslipidemia, heart failure, and arrhythmia are known consequences of some cancer therapies. This review provides an overview of the epidemiology, mechanism of action, monitoring, and management of these cardiovascular effects.

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Anti-cancer activity of NVP-TAE226, a potent dual FAK/IGF-IR kinase inhibitor, against pancreatic carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13162 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13162-13162 ◽

Cited By ~ 3

Author(s):

S. Hatakeyama ◽

D. Tomioka ◽

E. Kawahara ◽

N. Matsuura ◽

K. Masuya ◽

...

Keyword(s):

Cell Proliferation ◽

Pancreatic Carcinoma ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Proliferation ◽

Normal Cells ◽

P Glycoprotein ◽

Anti Cancer ◽

Cancer Activity

13162 Background: Focal adhesion kinase (FAK) is a non-receptor cytoplasmic tyrosine kinase that regulates multiple cell functions. Elevated expression levels of FAK have been detected in various tumor samples and are closely correlated with invasive potential. Activation of integrins and the growth factor receptors result in FAK autophosphorylation at Y397 and the presentation of suitable binding sites for proteins containing either SH2 or phosphotyrosine binding domains. Recent evidences suggest that FAK plays important roles in cancer cell proliferation and survival. IGF-IR function is required for tumor cell survival, but dispensable for survival of normal cells. Therefore, a dual inhibitor of both kinases may selectively block the growth, migration, and survival of FAK- and IGF-IR- expressing tumor cells compared to proliferating and migrating normal cells. Methods: In this study, anti-cancer activity of NVP-TAE226 that is identified as a potent and selective FAK inhibitor was evaluated in cancer cell lines panel and MIA PaCa-2 pancreatic carcinoma in vivo model. Results: Mean GI50 value of NVP-TAE226 against 37 cancer cell lines was 0.76 μmole/L. Inhibition of cancer cell proliferation was not affected by expression of P-glycoprotein, suggesting that NVP-TAE226 is not served as a substrate of P-glycoprotein. Oral administration of NVP-TAE226 efficiently inhibited MIA PaCa-2 human pancreatic tumor growth at all doses tested. Tumor stasis was observed at a dose of 30 mg/kg, qd for 7×/week and tumor regression was observed at a dose of 100 mg/kg, qd for 5×/week. All animals tolerated NVP-TAE226 treatment up to 100 mg/kg, 5×/wk, qd, po for 2 weeks with no body weight loss. Inhibition of downstream signaling such as phosphorylation of Akt at Serine473 was accompanied by inhibition of FAK phosphorylation in human pancreatic carcinoma cell lines. Conclusions: NVP-TAE226 is a novel class of selective and small molecule kinase inhibitors with a potent in vivo activity and potential therapeutic application. No significant financial relationships to disclose.

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A green chemistry approach for the synthesis of gold nanoconjugates that induce the inhibition of cancer cell proliferation through induction of oxidative stress and their in vivo toxicity study

Journal of Materials Chemistry B ◽

10.1039/c5tb00244c ◽

2015 ◽

Vol 3 (18) ◽

pp. 3820-3830 ◽

Cited By ~ 48

Author(s):

Sudip Mukherjee ◽

Mamatha Dasari ◽

Sumahitha Priyamvada ◽

Rajesh Kotcherlakota ◽

Vishnu Sravan Bollu ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Proliferation ◽

Gold Nanoparticles ◽

Green Chemistry ◽

Cancer Cell ◽

Cancer Therapeutics ◽

Toxicity Study ◽

Cancer Cell Proliferation ◽

Near Future

The synthesis and fabrication of green chemistry based biocompatible gold nanoparticles could be clinically effective towards cancer therapeutics in the near future.

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Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

Pharmaceuticals ◽

10.3390/ph14050470 ◽

2021 ◽

Vol 14 (5) ◽

pp. 470

Author(s):

Nirmala Tilija Pun ◽

Chul-Ho Jeong

Keyword(s):

Cell Proliferation ◽

Drug Resistance ◽

Drug Repurposing ◽

Synergistic Action ◽

Cancer Drug ◽

Cancer Cell Proliferation ◽

Cancer Drug Resistance ◽

Anti Cancer

Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.

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