CARP-1 functional mimetics are novel inhibitors of drug-resistant triple negative breast cancers.
Doxorubicin and Cisplatin are the frontline therapeutics for treatment of the triple negative breast cancers (TNBCs). Emergence of drug-resistance often contributes to failure of drugs and poor prognosis, and thus necessitates development of new and improved modalities to treat TNBCs. We generated and characterized chemotherapy-resistant TNBC cells following their culture in chronic presence of Doxorubicin or Cisplatin, and tested whether their viabilities were inhibited by a novel class of CARP- 1 functional mimetic (CFM) compounds. Analogs of parent compound CFM-4 were obtained through structure-activity based medicinal chemistry studies. CFM-4.16, a novel analog of CFM-4, caused superior inhibition of viability of TNBC cells when used in combination with doxorubicin. Doxorubicin and cisplatin inhibited viabilities of parental cells with GI50 dose of 0.02-0.1 μM and 1.65 μM, respectively. The GI50 dose of doxorubicin for doxorubicin-resistant TNBC cells was ≥ 10.0 μM. For Cisplatin-resistant cells, the GI50 dose of Cisplatin was ≥ 6-15.0 μM for MDA-MB-468 sublines and ≥ 150.0 μM for MDA-MB-231 sublines. CFM-4.16 inhibited viability of chemotherapy-resistant TNBC cells, in part by inhibiting oncogenic cMet activation and expression, stimulating CARP-1 expression, caspase-8 cleavage and apoptosis. CFM-4.16 pretreatment enhanced anti-TNBC efficacies of inhibitors of cMET (Tevatinib) or cSrc (Dasatinib). CFM-4.16 suppressed growth of resistant TNBC cells in soft agar as well as in three-dimensional suspension cultures derived from enriched, stem-like cells. Finally, a nanolipid formulation of CFM-4.16 in combination with doxorubicin had superior efficacy in inhibiting TNBC xenograft growth. Our findings collectively demonstrate therapeutic potential of CFM-4.16 for parental and drug-resistant TNBCs.
John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, 48201 USA.|Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201 USA.|Department of Oncology, Wayne State University, Detroit, MI 48201 USA.|Department of Pathology, Wayne State University, Detroit, MI 48201 USA.
Vino T
VT
Cheriyan
John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, 48201 USA.|Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201 USA.|Department of Oncology, Wayne State University, Detroit, MI 48201 USA.|Department of Pathology, Wayne State University, Detroit, MI 48201 USA.
Magesh
M
Muthu
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Ketan
K
Patel
John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, 48201 USA.|Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201 USA.|Department of Oncology, Wayne State University, Detroit, MI 48201 USA.|Department of Pathology, Wayne State University, Detroit, MI 48201 USA.
Sreeja
S
Sekhar
Vahlteich Medicinal Chemistry Core and College of Pharmacy, University of Michigan, Ann Arbor, MI 48109 USA.
Walajapet
W
Rajeswaran
Vahlteich Medicinal Chemistry Core and College of Pharmacy, University of Michigan, Ann Arbor, MI 48109 USA.
Scott D
SD
Larsen
Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201 USA.|Department of Oncology, Wayne State University, Detroit, MI 48201 USA.|Department of Pathology, Wayne State University, Detroit, MI 48201 USA.
Lisa
L
Polin
John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, 48201 USA.|Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201 USA.|Department of Oncology, Wayne State University, Detroit, MI 48201 USA.|Department of Pathology, Wayne State University, Detroit, MI 48201 USA.
Edi
E
Levi
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Mandip
M
Singh
John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, 48201 USA.|Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201 USA.|Department of Oncology, Wayne State University, Detroit, MI 48201 USA.|Department of Pathology, Wayne State University, Detroit, MI 48201 USA.
Arun K
AK
Rishi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000067558:Biological Mimicry; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C569107:1-(2-chlorobenzyl)-5'-phenyl-3'H-spiro(indoline-3,2'-(1,3,4)thiadiazol)-2-one; D051017:Apoptosis Regulatory Proteins; C477529:CCAR1 protein, human; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D013141:Spiro Compounds; D013830:Thiadiazoles; D004317:Doxorubicin
CARP-1; CFMs; apoptosis; mammospheres; resistant TNBCs
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