3-Ketone-4,6-diene ceramide analogs exclusively induce apoptosis in chemo-resistant cancer cells.
Multidrug-resistance is a major cause of cancer chemotherapy failure in clinical treatment. Evidence shows that multidrug-resistant cancer cells are as sensitive as corresponding regular cancer cells under the exposure to anticancer ceramide analogs. In this work we designed five new ceramide analogs with different backbones, in order to test the hypothesis that extending the conjugated system in ceramide analogs would lead to an increase of their anticancer activity and selectivity towards resistant cancer cells. The analogs with the 3-ketone-4,6-diene backbone show the highest apoptosis-inducing efficacy. The most potent compound, analog 406, possesses higher pro-apoptotic activity in chemo-resistant cell lines MCF-7TN-R and NCI/ADR-RES than the corresponding chemo-sensitive cell lines MCF-7 and OVCAR-8, respectively. However, this compound shows the same potency in inhibiting the growth of another pair of chemo-sensitive and chemo-resistant cancer cells, MCF-7 and MCF-7/Dox. Mechanism investigations indicate that analog 406 can induce apoptosis in chemo-resistant cancer cells through the mitochondrial pathway. Cellular glucosylceramide synthase assay shows that analog 406 does not interrupt glucosylceramide synthase in chemo-resistant cancer cell NCI/ADR-RES. These findings suggest that due to certain intrinsic properties, ceramide analogs' pro-apoptotic activity is not disrupted by the normal drug-resistance mechanisms, leading to their potential use for overcoming cancer multidrug-resistance.
Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, United States.
Adharsh P
AP
Ponnapakam
Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, United States.
Jiawang
J
Liu
College of Pharmacy Basic Pharmaceutical Sciences, University of Louisiana at Monroe, 1800 Bienville, Monroe, LA 71209, United States.
Kaustubh N
KN
Bhinge
Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, United States.
Barbara A
BA
Drew
Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, United States.
Tony L
TL
Wang
Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, United States.
James W
JW
Antoon
Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, United States.
Thong T
TT
Nguyen
Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, United States.
Patrick S
PS
Dupart
College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
Yuji
Y
Wang
College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
Ming
M
Zhao
College of Pharmacy Basic Pharmaceutical Sciences, University of Louisiana at Monroe, 1800 Bienville, Monroe, LA 71209, United States.
Yong-Yu
YY
Liu
Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, United States. Electronic address: mforooze@xula.edu.
Maryam
M
Foroozesh
Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, United States.
Barbara S
BS
Beckman
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D044482:Benzeneacetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D007659:Ketones / Q000737:chemistry*; D061986:MCF-7 Cells; D008968:Molecular Conformation
D000970:Antineoplastic Agents; D044482:Benzeneacetamides; D002518:Ceramides; D007659:Ketones; C000591912:N-(1-hydroxy-3-oxoheptadeca-4,6-dien-2-yl)-2-phenylacetamide; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase
Anti-cancer drugs; Ceramide; Glucosylceramide synthase (GCS); Multidrug resistance; P-glycoprotein