title: Polyphenol-rich extract of Pimenta dioica berries (Allspice) kills breast cancer cells by autophagy and delays growth of triple negative breast cancer in athymic mice.
abstract: Bioactive compounds from edible plants have limited efficacy in treating advanced cancers, but they have potential to increase the efficacy of chemotherapy drugs in a combined treatment. An aqueous extract of berries of Pimenta dioica (Allspice) shows promise as one such candidate for combination therapy or chemoprevention. An aqueous extract of Allspice (AAE) was tested against human breast cancer (BrCa) cells in vitro and in vivo. AAE reduced the viability and clonogenic growth of several types of BrCa cells (IC50 ≤ 100 μg/ml) with limited toxicity in non-tumorigenic, quiescent cells (IC50 >200 μg/ml). AAE induced cytotoxicity in BrCa was inconsistent with apoptosis, but was associated with increased levels of autophagy markers LC3B and LC3B-positive puncta. Silencing the expression of autophagy related genes (ATGs) prevented AAE-induced cell death. Further, AAE caused inhibition of Akt/mTOR signaling, and showed enhanced cytotoxicity when combined with rapamycin, a chemotherapy drug and an inhibitor of mTOR signaling. Oral administration (gavage) of AAE into athymic mice implanted with MDA-MB231 tumors inhibited tumor growth slightly but not significantly (mean decrease ~ 14%, p ≥ 0.20) if mice were gavaged post-tumor implant. Tumor growth showed a significant delay (38%) in tumor palpability and growth rate (time to reach tumor volume ≥ 1,000 mm3) when mice were pre-dosed with AAE for two weeks. Analysis of tumor tissues showed increased levels of LC3B in AAE treated tumors, indicating elevated autophagic tumor cell death in vivo in treated mice. These results demonstrate antitumor and chemo-preventive activity of AAE against BrCa and potential for adjuvant to mTOR inhibition.
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Departments of Urology and Radiation Oncology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Nagarajarao
authors.initials: N
authors.lastname: Shamaladevi
authors.affiliation: Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, Texas, USA.
authors.forename: Guddadarangavvanahally K
authors.initials: GK
authors.lastname: Jayaprakasha
authors.affiliation: Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, Texas, USA.
authors.forename: Bhimu S
authors.initials: BS
authors.lastname: Patil
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, USA.|Departments of Urology and Radiation Oncology, Miller School of Medicine, University of Miami, Miami, Florida, USA.|Research Service, Bruce Carter Memorial Veterans Health Administration Medical Center, Miami, Florida, USA.
authors.forename: Bal L
authors.initials: BL
authors.lastname: Lokeshwar
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D027841:Pimenta / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D010936:Plant Extracts; D034741:RNA, Small Interfering; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes
keywords: autophagy; breast cancer; chemo dietary-cancer prevention; chemoprevention; mTOR signaling